Beyond GLP-1: underexplored peptide–receptor systems as the next frontier in drug discovery

1 Introduction

For much of modern drug development, peptide therapeutics were regarded as biologically compelling yet pharmacologically impractical. Rapid enzymatic degradation limited oral bioavailability, short plasma half-lives, and pleiotropic signaling profiles confined peptides largely to hormone replacement therapies or niche endocrine indications. This perception persisted despite extensive evidence that endogenous peptides regulate virtually every major physiological system, including metabolism, cardiovascular homeostasis, neuroendocrine signaling, immune modulation, and tissue repair.

The clinical and commercial success of glucagon-like peptide-1 (GLP-1) receptor agonists has decisively overturned this paradigm. Importantly, this success did not arise from the discovery of new biology, but from the translational maturation of a peptide system that had been characterized for decades. GLP-1 was identified in the early 1980s, and its insulinotropic and anorectic properties were rapidly established; however, clinically viable GLP-1 receptor agonists did not emerge until advances in peptide stabilization, delivery, and dosing strategies were achieved (Campbell and Drucker, 2013; Drucker, 2018).

The delayed translation of GLP-1 illustrates a critical principle: biological validity alone is insufficient for therapeutic success. Early GLP-1 development efforts were hindered by rapid degradation by dipeptidyl peptidase-4, short duration of action, and gastrointestinal intolerance at supraphysiologic exposure levels. These challenges were ultimately overcome through molecular modification, long-acting formulations, and a more sophisticated understanding of receptor pharmacology, including biased agonism and dose–exposure relationships (Müller et al., 2019).

This historical trajectory strongly suggests that GLP-1 should not be viewed as an isolated success, but rather as a prototype for a much larger class of peptide–receptor systems whose translational potential remains unrealized. Numerous endogenous peptides meet fundamental criteria for druggability, including defined receptors, dose-dependent physiological effects, and genetic or pharmacologic validation in preclinical models. Their neglect has often resulted from early adverse events attributable to poor pharmacokinetic design, incomplete receptor mapping, or the absence of enabling technologies now considered routine, such as long-acting peptide conjugation, tissue-selective targeting, and signal-bias optimization.

At the same time, it is essential to recognize the limits of the GLP-1 paradigm as a universal model. GLP-1 possesses unique properties, including glucose-dependent insulin secretion, which confer a broad therapeutic index and reduce the risk of hypoglycemia. Not all peptide systems share these properties, and some may fail due to genuine on-target toxicity that cannot be mitigated solely through pharmacologic engineering. Accordingly, GLP-1 should be regarded as a heuristic example rather than a prescriptive template for all peptide therapeutics.

This review advances the central thesis that many peptide–receptor systems remain underexplored not because their biology is unsound, but because they were evaluated using outdated translational frameworks. By reassessing these systems through the lens of modern peptide pharmacology and systems biology, this review seeks to distinguish between failed biology and failed pharmacology, identify the classes of peptides most amenable to renewed development, and articulate principles that can guide future discovery efforts.

1.1 Review methodology and scope

This review constitutes a narrative and conceptual synthesis rather than a systematic meta-analysis. Primary research articles were prioritized where available, particularly for mechanistic and translational claims. For peptide systems with limited clinical data, authoritative review articles and consensus statements were used to contextualize findings and delineate areas of uncertainty. The scope of the review is intentionally selective rather than exhaustive, focusing on peptide–receptor systems that demonstrate biological plausibility, mechanistic coherence, and unmet therapeutic potential, yet lack approved therapeutic analogs or advanced clinical programs.

1.2 Safety considerations and the limits of the GLP-1 analogy

The success of GLP-1 receptor agonists should not obscure legitimate safety considerations associated with chronic peptide therapy. Postmarketing surveillance and observational studies have reported cases of pancreatitis in patients receiving GLP-1 receptor agonists, although a causal relationship remains debated and confounded by underlying disease risk factors (Drucker, 2018). However, large meta-analyses and regulatory reviews have not established a definitive causal relationship.

In addition, rodent studies demonstrating thyroid C-cell hyperplasia and tumors led to class warnings and contraindications in susceptible populations; the relevance of these findings to human risk remains uncertain and has not been definitively established in clinical trials or epidemiologic studies (Müller et al., 2019).

These considerations underscore the importance of evidence-based safety assessment and cautious extrapolation when evaluating other peptide–receptor systems. They also highlight a recurring pattern in peptide drug development: early safety signals, particularly those observed at supraphysiologic exposure levels or in non-human models, have frequently led to premature abandonment of otherwise biologically compelling targets.

Taken together, the GLP-1 experience illustrates both the promise and the limits of peptide pharmacology. It demonstrates that complex endocrine signaling can be harnessed therapeutically when molecular design, dosing, and patient selection are appropriately aligned, while also emphasizing the necessity of rigorous safety evaluation. These lessons provide a critical framework for reassessing peptide–receptor systems that were historically abandoned or underexplored. Figure 1 illustrates the progression from endogenous peptide discovery through receptor identification, physiological validation, pharmacologic engineering, and clinical translation. Underexplored peptide systems frequently encounter attrition after biological validation but before pharmacologic optimization, whereas GLP-1 progressed through these stages following the introduction of enabling technologies.

2 Defining “underexplored” peptide–receptor systems

In the context of peptide drug discovery, the term ‘underexplored’ is often used imprecisely to denote novelty, obscurity, or a lack of published literature. In this review, however, underexplored peptide–receptor systems are defined not by limited biological knowledge, but by a persistent mismatch between biological validation and pharmacologic exploitation. Many peptide systems discussed herein have been repeatedly shown to exert robust physiological effects in vivo, often across multiple species, yet lack approved therapeutic analogs or advanced clinical programs despite decades of investigation.

This distinction is critical for scientific integrity. A peptide system may be well characterized at the molecular and physiological levels while remaining translationally underdeveloped due to factors unrelated to biological relevance. These include early pharmacokinetic limitations, inadequate receptor selectivity, poorly chosen clinical endpoints, or the absence of enabling technologies at the time of initial evaluation. As illustrated by the GLP-1 experience, such limitations can delay translation by decades without invalidating the underlying biology (Campbell and Drucker, 2013; Drucker, 2018).

Underexploration, as defined here, therefore reflects historical and technological context rather than intrinsic therapeutic inadequacy. This perspective contrasts with failed targets, for which rigorous clinical evaluation has demonstrated unacceptable on-target toxicity or lack of efficacy at therapeutically relevant exposures. Disentangling these two categories—failed biology versus failed pharmacology—is essential to avoid repeating historical errors and to prioritize peptide systems with realistic translational potential.

2.1 Criteria for identifying underexplored peptide systems

To operationalize this definition, peptide–receptor systems considered underexplored in this review meet several criteria. First, the endogenous peptide must exhibit reproducible physiological effects supported by genetic, pharmacologic, or observational evidence. Second, the cognate receptor must be known or plausibly identifiable, enabling mechanistic interrogation and rational drug design. Third, the system must lack approved therapeutics despite biological validation or have had development efforts abandoned at an early stage due to non-biological limitations.

Importantly, these criteria intentionally exclude peptide systems for which multiple well-designed human studies have demonstrated a lack of efficacy or unacceptable safety profiles. The goal is not to resurrect targets conclusively shown to fail in humans, but to re-evaluate systems whose translational assessment was incomplete or constrained by outdated methodologies. A concrete example that clarifies this boundary is gastrin: multiple adequately powered human trials demonstrated that gastrin-based therapies failed to preserve beta-cell function in type 2 diabetes, and development was largely discontinued by approximately 2010. Under the framework applied here, gastrin would be classified as a failed target rather than an underexplored one, because its abandonment followed rigorous human evaluation. By contrast, peptides such as PYY and apelin were discontinued primarily due to formulation limitations or tolerability at supraphysiologic doses—pharmacologic rather than biological failures—and therefore meet criteria for re-evaluation.

2.2 Historical reasons for underexploration

Across peptide systems, several recurring factors have contributed to underexploration. One of the most common has been unfavorable pharmacokinetics, particularly rapid enzymatic degradation and short duration of action. Prior to the widespread adoption of lipidation, albumin binding, and fusion strategies, many peptides were dismissed as clinically impractical solely because of their dosing frequency. GLP-1 itself exemplifies this phenomenon, as early native peptide formulations required continuous infusion to achieve sustained efficacy.

A second factor has been pleiotropy, which was historically interpreted as a liability rather than a potential advantage. Peptides that influenced multiple physiological pathways were often deemed “too complex” for therapeutic development, particularly when early studies revealed off-target effects at supraphysiologic doses. Modern concepts of biased agonism and tissue-selective signaling have reframed pleiotropy as a feature that can be modulated rather than avoided outright (Kenakin, 2019).

A third factor has been incomplete receptor characterization. Several peptides with strong physiological phenotypes were identified before their receptors were cloned or fully characterized, limiting structure–activity relationship studies and medicinal chemistry optimization. In other cases, receptor families were poorly understood, leading to concerns about cross-reactivity or unintended signaling. Advances in receptor de-orphanization, structural biology, and computational modeling have substantially reduced these barriers, warranting renewed evaluation of such systems.

Finally, early clinical failures were often overinterpreted. Adverse events observed at high exposure levels or in small, poorly controlled trials were sometimes taken as definitive evidence against a target. The subsequent success of GLP-1 receptor agonists, despite early gastrointestinal intolerance and safety concerns, illustrates how such signals may be manageable through improved formulation and dosing rather than indicative of fundamental biological unsuitability.

2.3 Categories of underexplored peptide–receptor systems

To provide a structured framework for subsequent sections, the major categories of underexplored peptide–receptor systems examined in this review are summarized in Table 1, which is cited here to contextualize the scope and rationale of inclusion. These categories are organized by physiological domain and translational barrier rather than by peptide family or receptor class, reflecting the cross-cutting nature of underexploration.

TABLE 1. Representative categories of underexplored peptide–receptor systems and primary barriers to therapeutic development.

Table 1 illustrates that the most significant obstacles to progress across these systems have not been a lack of physiological relevance, but unresolved pharmacologic, technological, or conceptual challenges. Importantly, many of these challenges are now tractable using contemporary approaches to peptide engineering, receptor biology, and translational trial design.

2.4 Implications for drug discovery strategy

Recognizing underexploration as a product of historical context rather than biological inadequacy has important implications for drug discovery strategy. It suggests that substantial therapeutic value may reside in revisiting known peptide systems with modern tools, rather than focusing exclusively on the discovery of entirely new ligands. This approach aligns with broader trends toward de-risking early-stage development by leveraging validated biology and emphasizes the importance of translational rigor over novelty alone.

The sections that follow apply this framework to specific physiological domains, beginning with metabolic and energy-balance peptides beyond the incretin family. Each system is evaluated with explicit attention to the evidence supporting biological relevance, the reasons for historical underexploration, and the translational questions that must be addressed to enable renewed development.

3 Why underexplored peptide–receptor systems matter now

The renewed relevance of underexplored peptide–receptor systems is not driven solely by incremental advances in molecular biology, but by a convergence of technological, conceptual, and clinical developments that fundamentally alter their translational feasibility. Many peptide systems were first evaluated in an era when short half-lives, poor oral bioavailability, and limited receptor selectivity were viewed as insurmountable barriers. Today, these same limitations are increasingly manageable and, in some cases, strategically exploitable due to advances in peptide engineering, receptor pharmacology, and clinical trial design.

A central insight emerging from the GLP-1 experience is that biological pleiotropy does not preclude therapeutic utility. Early skepticism toward GLP-1 receptor agonists centered on gastrointestinal intolerance, concerns about pancreatitis, and the perception that widespread receptor expression would lead to unacceptable off-target effects. Subsequent clinical success demonstrated that these liabilities could be mitigated through slower absorption kinetics, extended dosing intervals, and careful titration, ultimately allowing the beneficial metabolic effects to dominate the risk–benefit profile (Drucker, 2018; Müller et al., 2019). This lesson is directly applicable to other peptide systems that were abandoned following early signals of complexity or tolerability issues.

3.1 Enabling technologies in modern peptide pharmacology

One of the most important developments reshaping peptide drug discovery has been the widespread adoption of long-acting peptide design strategies. Chemical modifications such as lipidation (first applied therapeutically to insulin in the 1990s), PEGylation (established as a platform technology in the early 2000s), and reversible albumin binding have transformed peptides from short-lived signaling molecules into durable therapeutics suitable for weekly or even monthly administration (Langer, 1998; Sato et al., 2004). These approaches not only extend half-life, but also flatten peak–trough exposure profiles, reducing dose-dependent adverse effects that previously limited development.

In parallel, advances in formulation science and delivery technologies have expanded the feasible routes of peptide administration. While injectability remains common, oral, transdermal, and implantable delivery strategies are increasingly viable for selected peptides (Fosgerau and Hoffmann, 2015). These advances weaken one of the most frequently cited historical objections to peptide therapeutics and broaden the range of clinical contexts in which they can be realistically deployed.

Equally transformative has been the maturation of receptor pharmacology as a discipline. The recognition that ligands can differentially bias receptor signaling toward distinct intracellular pathways has reframed how efficacy and toxicity are understood. Rather than viewing receptor activation as a binary event, biased agonism allows selective amplification of therapeutically desirable signaling while minimizing pathways associated with adverse effects (Kenakin, 2019). This concept is particularly relevant for peptides that engage widely expressed GPCRs, where early development efforts may have failed due to non-selective activation. It should be acknowledged, however, that the translational impact of biased agonism remains incompletely validated in clinical settings. Even within the GLP-1 class, clear differentiation in outcomes attributable to differential signaling bias has been limited in practice (Wootten et al., 2018). The principle remains intellectually compelling and mechanistically supported, but clinical demonstration of superiority based on signaling bias alone has yet to be robustly established for most peptide targets. Concrete examples of biased agonism that have clearly improved therapeutic outcomes include the development of β-arrestin–biased angiotensin II receptor ligands (which showed reduced hypertension-related adverse effects in preclinical models) and carfentanil-class opioid analogs designed to preferentially engage G-protein over arrestin pathways, thereby reducing respiratory depression (Schmid et al., 2017).

3.2 From single-target optimization to rational polypharmacology

Another major shift influencing the relevance of underexplored peptide systems is the growing acceptance of rational polypharmacology. Traditional drug discovery emphasized high selectivity for a single target, often at the expense of physiological relevance. However, complex diseases such as obesity, type 2 diabetes, and neurodegenerative disorders are increasingly understood as network-level dysregulations rather than single-pathway failures.

The clinical success of dual and triple incretin agonists has validated the concept that engaging multiple complementary pathways within a single molecular framework can yield superior efficacy without proportionally increasing toxicity (Finan et al., 2016). Many endogenous peptides naturally exhibit multi-receptor activity, a feature that was historically viewed as a liability but may instead reflect evolutionary optimization for coordinated physiological control. Underexplored peptides that activate multiple receptors or signaling cascades may therefore be particularly well suited to modern therapeutic strategies that embrace controlled polypharmacology.

3.3 Improved tools for mechanistic validation and risk de-risking

Technological advances have also improved the ability to de-risk peptide systems earlier in development. High-resolution structural biology, including cryo-electron microscopy and computational modeling, has enabled detailed mapping of peptide–receptor interactions, informing rational design and selectivity optimization. Clinically validated examples of in silico and structure-based approaches contributing directly to approved therapeutics include the development of HIV protease inhibitors in the 1990s—the first drugs designed using computational structure–activity relationships—and the more recent application of GPCR crystal structures to guide ligand optimization for receptors, including the β2-adrenoceptor and GLP-1 receptor (Kobilka and Deupi, 2007; Jazayeri et al., 2017). For peptide therapeutics specifically, published GLP-1 receptor cryo-EM structures have retrospectively illuminated the binding mode of approved agonists and are actively informing next-generation analog design (Zhao et al., 2020). Concurrently, advances in genetics and functional genomics have strengthened causal inference by linking peptide pathways to human phenotypes through loss-of-function variants, expression quantitative trait loci, and Mendelian randomization studies.

These tools enable peptide systems to be evaluated with a level of mechanistic precision unavailable when many were first investigated. In principle, it is increasingly possible to distinguish between liabilities intrinsic to a biological pathway and those arising from suboptimal molecular design or experimental context. However, this distinction is not always achievable in practice. For example, in the case of amylin biology, significant translational gaps between rodent and human systems persist, the optimal receptor selectivity profile for clinical use remains unclear, and molecules continue to advance in clinical development despite these uncertainties (Hollander et al., 2020). This underscores that mechanistic tools improve our capacity for rational design but do not eliminate biological uncertainty, and that translational risk must still be assessed empirically. Nonetheless, these tools provide a meaningful foundation for prioritizing which underexplored systems merit renewed investment.

3.4 Changing clinical and regulatory expectations

Finally, shifts in clinical and regulatory expectations have altered the landscape in which peptide therapeutics are evaluated. Regulatory agencies increasingly recognize the value of surrogate endpoints, adaptive trial designs, and biomarker-driven patient stratification, particularly in areas of high unmet need. These developments favor therapeutic modalities, such as peptides, that can be mechanistically linked to disease pathways and monitored through pharmacodynamic readouts.

Moreover, the success of incretin-based therapies has recalibrated tolerance for certain classes of adverse effects when balanced against substantial clinical benefit. Gastrointestinal side effects that might have doomed earlier peptide programs are now considered manageable in the context of significant weight loss, metabolic improvement, or disease modification. This shift does not diminish the importance of safety, but it underscores the need to evaluate peptide systems within an appropriate therapeutic context rather than through overly conservative early-stage filters.

3.5 Strategic implications

Taken together, the developments described above—namely, the maturation of long-acting peptide design, the conceptual shift toward rational polypharmacology, the availability of improved mechanistic validation tools, and the evolution of clinical and regulatory expectations—suggest that the present moment represents an inflection point for underexplored peptide–receptor systems. The convergence of enabling technologies, conceptual shifts toward polypharmacology, improved mechanistic tools, and evolving regulatory frameworks has fundamentally altered the translational calculus. Peptide systems previously deemed too complex, too pleiotropic, or too impractical may now be among the most promising candidates for next-generation therapeutics.

The following sections apply this perspective to specific physiological domains, beginning with metabolic and energy-balance peptides beyond the incretin family. These systems illustrate how biologically validated peptides can be reassessed using modern pharmacologic principles to uncover therapeutic opportunities previously obscured.

4 Metabolic and energy-balance peptides beyond the incretin paradigm

While incretin biology has dominated metabolic drug development over the past decade, incretins represent only a subset of the endogenous peptide networks governing energy balance. Multiple peptide–receptor systems regulate glucose utilization, lipid handling, mitochondrial efficiency, and substrate partitioning independently of insulin secretion. These non-incretin metabolic peptides frequently exert effects on peripheral tissues such as skeletal muscle, adipose tissue, liver, and vasculature, and often engage receptors distinct from those targeted by current therapies. Despite compelling biological validation, many of these systems remain underdeveloped as pharmacologic targets.

A recurring theme across non-incretin metabolic peptides is that early development efforts were constrained by pleiotropy, cardiovascular effects, or incomplete receptor characterization rather than by lack of metabolic relevance. The following sections examine representative systems—apelin, spexin, meteorin-like protein (METRNL), and oxyntomodulin—with explicit attention to the evidence supporting their metabolic roles, the reasons for historical underexploration, and the translational questions that remain unresolved.

4.1 The Apelin–APJ axis

Apelin was identified as the endogenous ligand for the APJ receptor, a G protein–coupled receptor structurally related to the angiotensin II type 1 receptor but functionally distinct from the renin–angiotensin system (Tatemoto et al., 1998). Apelin and its receptor are widely expressed in adipose tissue, skeletal muscle, heart, and endothelium, with expression dynamically regulated by nutritional and metabolic state (Boucher et al., 2005). In preclinical models, apelin enhances glucose uptake in skeletal muscle via activation of AMP-activated protein kinase, improves insulin sensitivity, and increases mitochondrial oxidative capacity, supporting its role as an endogenous insulin-sensitizing hormone (Dray et al., 2008).

Despite these favorable metabolic effects, enthusiasm for apelin-based therapeutics waned due to its potent cardiovascular actions, including vasodilation and positive inotropy. While these effects may be beneficial in selected cardiovascular indications, they raised concerns regarding hypotension and hemodynamic instability when considered for chronic metabolic disease. Subsequent studies demonstrated that apelin signaling is highly context dependent, with differential coupling to Gα_i, Gα_q, and β-arrestin pathways depending on ligand structure, receptor density, and tissue environment (Murali and Aradhyam, 2023). This insight reframes some early safety concerns as issues of signaling bias and exposure. However, it is important to note that this interpretation is incomplete. Several small molecules targeting the APJ receptor have progressed to clinical evaluation but were discontinued due to insufficient superiority over the standard of care. More recently, a small-molecule APJ agonist partnered with BioAge failed in clinical development due to hepatotoxicity unrelated to target engagement, highlighting that off-target toxicity can arise independently of the signaling bias hypothesis (Ryffel et al., 2023). Concurrently, Structure Therapeutics is advancing an APJ-targeting molecule into Phase 2 evaluation for obesity, suggesting that the target remains of clinical interest when candidate molecules are appropriately selected. Together, these developments indicate that apelin/APJ represents a system where the translational story is still evolving rather than resolved.

Translationally, the apelin–APJ system illustrates a broader challenge for metabolic peptides with cardiovascular overlap: indication-specific development is likely required. Acute or tissue-restricted APJ activation may be appropriate for cardiometabolic indications, whereas chronic systemic exposure may be unsuitable without biased or targeted agonists. These considerations suggest that apelin is underexplored, not because of weak biology, but because pharmacologic refinement was insufficient at the time of early evaluation.

4.2 Spexin and galanin receptor signaling

Spexin is a highly conserved 14-amino-acid peptide identified through bioinformatic analysis of the human genome. It is expressed in both central and peripheral tissues and has been implicated in the regulation of food intake, lipid metabolism, and body weight (Lv et al., 2019). Mechanistically, spexin signals primarily through galanin receptor subtypes GALR2 and GALR3, receptors with complex roles in nociception, mood regulation, and metabolic control.

In animal models, spexin administration reduces food intake, suppresses adipogenesis, and improves lipid profiles. Observational studies in humans report lower circulating spexin levels in obesity and metabolic syndrome, supporting its role as an endogenous metabolic regulator rather than a stress-induced peptide (Lv et al., 2019). However, early translational efforts were complicated by overlap between metabolic and neurobehavioral effects, raising concerns about central nervous system liabilities.

More recent analyses suggest that spexin’s metabolic actions may be dissociable from its nociceptive or affective effects through receptor subtype selectivity and dosing strategies (Kim et al., 2014). Species differences in galanin receptor distribution and signaling remain an important translational caveat, underscoring the need for careful human validation. Nevertheless, spexin exemplifies a peptide whose underexplored status reflects concerns about pleiotropy rather than a lack of metabolic relevance.

4.3 Meteorin-like protein (METRNL) and exercise-induced endocrinology

Meteorin-like protein (METRNL) occupies a distinct conceptual niche within metabolic peptide biology. Initially identified as a secreted factor induced by exercise and cold exposure, METRNL promotes energy expenditure and improves glucose tolerance through mechanisms involving immune–adipose crosstalk and beige adipocyte activation (Rao et al., 2014). Unlike apelin or spexin, METRNL’s receptor has not yet been definitively identified, placing it among ligands whose translational development is constrained by incomplete mechanistic understanding.

The physiological profile of METRNL is nevertheless highly attractive. It appears to act as an exercise-responsive endocrine signal that enhances metabolic flexibility without directly suppressing appetite or altering central satiety circuits. Human observational studies examining circulating METRNL levels have produced heterogeneous results, reflecting differences in study design, metabolic state, and assay methodology. For example, El-Lebedy (2019) reported reduced circulating METRNL levels in individuals with type 2 diabetes and obesity compared with controls, whereas Dadmanesh et al. (2019) found elevated METRNL levels in insulin-resistant subjects, underscoring the inconsistency across cohorts. These inconsistencies do not negate biological relevance but rather highlight the challenges of translating exercise-induced endocrine signals into static biomarkers.

From a drug-development perspective, METRNL illustrates the limitations of receptor-centric paradigms. While receptor identification would facilitate rational design, translational progress may also be achieved through phenotypic approaches that focus on reproducible metabolic outcomes. Advances in receptor de-orphanization, including functional genomics and computational ligand–receptor matching, may ultimately unlock METRNL’s full therapeutic potential.

4.4 Oxyntomodulin and natural dual agonism

Oxyntomodulin, a peptide derived from the proglucagon gene alongside GLP-1 and glucagon, provides a compelling example of endogenous polypharmacology. Oxyntomodulin acts as a dual agonist at GLP-1 and glucagon receptors, contributing to postprandial satiety while simultaneously increasing energy expenditure (Cohen et al., 2003). Early human studies demonstrated modest weight loss and appetite suppression, but development was curtailed due to concerns regarding glucagon-mediated hyperglycemia and cardiovascular effects.

The subsequent clinical success of engineered dual and triple incretin agonists has fundamentally altered the interpretation of these early findings. Rather than representing an unsafe signaling profile, oxyntomodulin’s dual agonism can be understood as a naturally evolved strategy for coordinated metabolic control. Modern pharmacologic approaches allow quantitative receptor engagement to be balanced, mitigating liabilities while preserving efficacy (Finan et al., 2016).

Oxyntomodulin, therefore, occupies an important conceptual position in this review. It is not strictly unexplored, nor is it a failed target. Instead, it exemplifies how endogenous peptides exhibiting multi-receptor activity were historically disadvantaged by a development paradigm that prioritized single-target selectivity over physiological relevance.

Collectively, the systems summarized in Table 2 demonstrate that the metabolic peptide landscape beyond incretins is rich in validated biology but limited in translational follow-through. Early signals of complexity, pleiotropy, or tolerability frequently discouraged further development, despite the possibility that these features could be harnessed through modern pharmacologic strategies. The following section extends this analysis to appetite, satiety, and behavioral peptides, where similar dynamics have constrained progress despite strong physiological validation.

TABLE 2. Pharmacologically underexploited metabolic peptide–receptor systems beyond incretins: native peptide pharmacology underdeveloped despite validated biology.

5 Appetite, satiety, and behavioral peptide systems revisited

Regulation of appetite and feeding behavior represents one of the most extensively investigated yet paradoxically undertranslated domains of peptide biology. Numerous gut- and brain-derived peptides exert potent anorectic or orexigenic effects, often with effect sizes comparable to or exceeding those of GLP-1 in preclinical models. Despite this, only a small subset of these systems has yielded approved therapeutics. A critical reassessment of historical failures reveals that many appetite-related peptide programs were abandoned not because their biology was flawed, but because early development conflated dose-dependent adverse effects or behavioral complexity with intrinsic target unsuitability (Lau et al., 2015; Tan et al., 2013).

The GLP-1 experience provides an instructive counterexample. Early GLP-1 receptor agonists were associated with prominent gastrointestinal side effects that initially raised concerns regarding tolerability. These effects were subsequently managed through slower absorption kinetics, extended dosing intervals, and careful titration, allowing therapeutic benefit to outweigh adverse events (Drucker, 2018). Similar dynamics are evident across other appetite-regulating peptide systems that warrant renewed evaluation under modern translational paradigms.

5.1 Peptide YY and the misinterpretation of early tolerability signals

Peptide YY (PYY) is secreted postprandially by enteroendocrine L cells and functions as a satiety hormone by activating Y2 receptors in the hypothalamus and brainstem, where it inhibits neuropeptide Y–mediated orexigenic signaling (Batterham et al., 2002). Early human studies demonstrated that exogenous administration of PYY3–36 significantly reduced food intake, providing strong physiological validation of its role in meal termination (Neary et al., 2005).

However, subsequent clinical trials reported high rates of nausea and vomiting, leading to the perception that PYY-based therapies were intrinsically intolerable. Notably, Gantz et al. (2007) reported that intravenous PYY3–36 administration in a Phase 1 study produced nausea in the majority of subjects at doses required for meaningful appetite suppression. In retrospect, these adverse effects closely mirror those observed during early GLP-1 development, where rapid systemic exposure and high peak concentrations produced unacceptable gastrointestinal symptoms. Unlike GLP-1, PYY development did not benefit from later advances in long-acting formulations or exposure smoothing, leading to premature abandonment of an otherwise biologically compelling target.

More recent studies suggest that PYY signaling interacts synergistically with GLP-1 and other satiety peptides, raising the possibility that lower-dose combination strategies could harness its anorectic effects while minimizing intolerance (De Silva et al., 2012; Mentis et al., 2021; Lean and Carraro, 2022). Importantly, the current clinical landscape reflects ongoing interest in this concept: while Roche has discontinued development of an NPY2R agonist, Gubra is advancing an NPY2R program in collaboration with Boehringer Ingelheim, suggesting that the hypothesis of pharmacologically optimized Y2 receptor engagement retains translational credibility. These findings underscore the importance of context-specific evaluation and combination paradigms for appetite-regulating peptides.

5.2 Oxyntomodulin as an endogenous polypharmacologic signal

As discussed in Section 4.4, it also plays a central role in appetite regulation in the context of metabolic peptides. Derived from the proglucagon gene, oxyntomodulin acts as a dual agonist at GLP-1 and glucagon receptors, promoting satiety and increasing energy expenditure (Cohen et al., 2003). Early clinical studies demonstrated modest weight loss and appetite suppression, but development was limited by concerns regarding glucagon receptor–mediated hyperglycemia and cardiovascular effects.

The subsequent clinical success of engineered dual and triple incretin agonists has reframed these concerns. Rather than representing a liability, oxyntomodulin’s dual-receptor activity may reflect an evolutionarily optimized mechanism for coordinated energy balance. Modern pharmacologic approaches allow the relative contribution of each receptor to be quantitatively tuned, mitigating adverse effects while preserving efficacy (Finan et al., 2016). As such, oxyntomodulin exemplifies how endogenous peptides exhibiting multi-receptor activity were disadvantaged by earlier single-target development paradigms.

5.3 Central neuropeptides and the behavioral dimension of feeding

Beyond gut-derived peptides, centrally expressed neuropeptides exert a profound influence over feeding behavior while simultaneously modulating stress, arousal, and reward pathways. Relaxin-3, a member of the relaxin peptide family predominantly expressed in the nucleus incertus, signals through the RXFP3 receptor and has been shown to stimulate food intake, alter stress responsiveness, and influence arousal states in animal models (Smith et al., 2014).

While its orexigenic effects may appear counterintuitive in the context of obesity treatment, relaxin-3 biology highlights an underappreciated dimension of appetite regulation: the integration of feeding behavior with emotional and cognitive states. Obesity, binge eating, and metabolic disease are increasingly recognized as conditions in which stress, affective dysregulation, and reward processing play central roles. From this perspective, peptides such as relaxin-3 may be more relevant to behavioral subtypes of metabolic disease than to weight loss per se.

Historically, such behavioral complexity was viewed as a disqualifying feature for drug development, as CNS-acting agents were associated with unpredictable neuropsychiatric liability and high regulatory barriers (Bray and Greenway, 2007; Aronne et al., 2011). However, advances in biased agonism, region-selective delivery, and patient stratification suggest that selective modulation of central peptide pathways may be achievable without broad neuropsychiatric disruption. These considerations argue for a more nuanced evaluation of centrally acting appetite peptides rather than categorical exclusion.

5.4 Translational lessons from abandoned appetite peptides

The historical trajectory of appetite and behavioral peptides reveals a recurring pattern: early development efforts often failed due to inadequate control over exposure, insufficient combination strategies, or overly conservative interpretations of side effects. In many cases, peptides were evaluated in isolation, at supraphysiologic doses, and without consideration of compensatory physiological mechanisms. Modern translational frameworks emphasize combination therapy, biomarker-guided dosing, and behavioral stratification, all of which may improve the therapeutic index of appetite-regulating peptides.

These insights are summarized in Table 3, which contextualizes representative appetite and behavioral peptides according to their physiological roles, developmental outcomes, and reasons for historical underexploration.

TABLE 3. Appetite and behavioral peptides with abandoned or pharmacologically underexploited therapeutic development: native peptide pharmacology underdeveloped.

While Table 1 through 3 categorize peptide systems by domain and developmental status, they do not fully capture the integrative nature of gut–brain signaling that underlies appetite and behavior. To illustrate these interactions, Figure 2 is presented below, and highlights points of convergence between underexplored peptides and established incretin pathways. This figure depicts the interconnected signaling pathways linking gut-derived peptides and central neuropeptides to hypothalamic and brainstem circuits controlling appetite, satiety, and behavior. Underexplored peptide systems are highlighted to illustrate points of convergence with established incretin pathways rather than isolation from them.

Collectively, the evidence reviewed in this section supports the conclusion that appetite and behavioral peptide systems have been constrained more by conceptual caution than by biological inadequacy. The same gastrointestinal side effects, central adaptations, and pleiotropic actions that once discouraged development are now recognized as manageable features of peptide pharmacology when appropriately contextualized. As the field increasingly embraces combination therapies and network-level interventions, revisiting these systems with modern tools may yield treatments that address not only caloric intake but also the behavioral and psychological dimensions of metabolic disease.

The following section extends this analysis to peptide systems that mediate bone–muscle–fat crosstalk, where the endocrine functions of traditionally structural tissues challenge conventional models of metabolic regulation.

6 Bone–muscle–fat crosstalk: endocrine functions beyond structural biology

For much of the 20th century, bone and skeletal muscle were viewed primarily as structural tissues with limited relevance to systemic metabolic regulation. This perspective has shifted substantially over the past 2 decades as accumulating evidence has demonstrated that both tissues secrete bioactive peptides that function as hormones, influencing glucose metabolism, energy expenditure, reproductive physiology, and aspects of aging. Despite this conceptual shift, peptide mediators of bone–muscle–fat crosstalk remain among the most underexplored endocrine systems, in part because their biology challenges traditional organ-based models of metabolism.

A defining feature of these systems is their integration of mechanical activity, structural integrity, and metabolic demand into unified endocrine networks. From a translational standpoint, this complexity has historically been viewed as a liability, particularly when human data appeared inconsistent or mechanistically incomplete (Mera et al., 2016). However, as with other peptide systems discussed in this review, such variability often reflects limitations in measurement, context, or study design rather than the absence of biological relevance.

6.1 Osteocalcin as an endocrine regulator of metabolism

Osteocalcin is the most extensively studied endocrine peptide derived from bone. Produced by osteoblasts and released into circulation—particularly in its undercarboxylated form—osteocalcin has been shown in animal models to enhance insulin secretion, improve insulin sensitivity, increase energy expenditure, and stimulate testosterone production (Lee et al., 2007; Oury et al., 2011). These findings reposition bone as an active endocrine organ rather than a passive target of hormonal regulation.

Mechanistically, osteocalcin signaling has been linked to the G protein–coupled receptor GPRC6A, providing a plausible pathway through which bone-derived signals influence pancreatic β-cells, adipocytes, and Leydig cells. Genetic and pharmacologic studies in mice support this framework, although receptor specificity and downstream signaling remain areas of active investigation.

Translation of osteocalcin biology to humans has been more heterogeneous. Epidemiologic studies report associations between circulating osteocalcin levels and markers of metabolic health, including glucose tolerance and insulin sensitivity, but effect sizes vary and causality remains uncertain (Confavreux et al., 2009). Importantly, these inconsistencies may reflect methodological limitations rather than biological absence. Measurement of undercarboxylated osteocalcin is technically challenging, with inter-assay variability and confounding by vitamin K status complicating interpretation.

Rather than undermining osteocalcin’s relevance, these challenges highlight the need for standardized assays, context-aware study designs, and pharmacologic tools that directly modulate osteocalcin signaling. As with GLP-1 prior to the advent of long-acting analogs, incomplete translational tools may explain the gap between strong preclinical biology and equivocal human data.

6.2 Irisin and the endocrinology of exercise

Irisin, a peptide cleaved from the transmembrane protein FNDC5 and released from skeletal muscle during exercise, represents a parallel and more controversial example of muscle-derived endocrine signaling. Initially described as a mediator of exercise-induced browning of white adipose tissue and increased energy expenditure, irisin was proposed as a candidate exercise-associated signaling molecule (Boström et al., 2012).

Subsequent debate regarding assay specificity, circulating concentrations, and translational relevance led to skepticism regarding irisin’s role in humans. However, independent lines of evidence continue to support involvement of FNDC5/irisin signaling in metabolic adaptation, bone remodeling, and neuroprotection, suggesting that early technical limitations may have obscured rather than invalidated its physiological relevance (Perakakis et al., 2017).

A key limitation for irisin translation remains the absence of a definitively identified receptor. This constraint has hindered structure–activity relationship studies and rational pharmacologic development. The receptor question is itself contentious: integrin αVβ5 has been proposed as a functional receptor mediating irisin effects on bone and adipose tissue, and αVβ3 integrin has been implicated in neuroprotective effects, yet neither has been universally accepted as a bona fide irisin receptor, and the binding affinities reported vary across experimental systems (Kim et al., 2018; Rao et al., 2021). The FNDC5 cleavage and secretion process itself remains incompletely understood: the efficiency of irisin shedding in humans appears lower than in rodents, partly explaining why rodent exercise phenotypes driven by irisin overexpression have been difficult to reproduce cleanly in human studies. Additionally, early controversy arose from questions about the detectability of irisin in human plasma using available immunoassays, with some studies questioning whether the signal reflected irisin or cross-reactive proteins; mass spectrometry-based methods have since confirmed circulating irisin in humans but at lower concentrations than initially reported (Jedrychowski et al., 2015). Clinical biomarker studies have produced heterogeneous associations between circulating irisin levels and indices of metabolic health, exercise capacity, and bone density across different populations, with effect sizes and directions varying by sex, age, and comorbidity status (Perakakis et al., 2017). Despite these limitations, irisin exemplifies a broader class of exercise-responsive peptides whose endocrine effects are context-dependent and may be poorly captured by static circulating measurements. Advances in receptor de-orphanization, spatial transcriptomics, and functional screening may ultimately clarify irisin’s mechanism of action and unlock its translational potential.

6.3 METRNL and immune–metabolic coupling

In Section 4.3, Meteorin-like protein (METRNL) was discussed in the context of metabolic peptides, which also occupies a position at the intersection of muscle, adipose tissue, and immune signaling. Induced by exercise and cold exposure, METRNL promotes beige adipocyte formation and enhances glucose tolerance through immune-mediated mechanisms (Rao et al., 2014). These findings suggest a role for METRNL in coordinating adaptive thermogenesis and metabolic flexibility.

As with irisin, METRNL’s receptor has not been definitively identified, limiting conventional drug development strategies. Human studies examining circulating METRNL levels have produced heterogeneous results, reflecting differences in metabolic state, physical activity, and assay methodology. Importantly, such variability does not negate biological relevance, but rather underscores the challenge of translating dynamic, context-sensitive endocrine signals into static biomarkers.

From a strategic perspective, METRNL illustrates the limitations of purely receptor-centric approaches to peptide drug discovery. Phenotypic outcomes—such as improved insulin sensitivity or enhanced thermogenesis—may provide more robust translational anchors than circulating peptide levels alone. This perspective aligns with emerging interest in exercise-mimetic and immunometabolic therapies that target network-level adaptations rather than single molecular nodes.

6.4 Translational challenges and opportunities

The peptide systems mediating bone–muscle–fat crosstalk share several translational challenges. Human data are often associative rather than interventional, assays lack standardization, and receptor mechanisms may be incomplete or contested. However, these challenges are not unique to this domain and mirror those faced by other peptide systems prior to successful translation.

Crucially, these peptides offer a conceptual alternative to appetite-centric approaches for metabolic disease. Rather than suppressing caloric intake, they may enhance substrate utilization, preserve lean mass, and improve metabolic resilience—features particularly relevant to aging populations, where sarcopenia, osteoporosis, and insulin resistance frequently coexist.

These considerations are summarized in Table 4, which contextualizes key bone- and muscle-derived peptides by origin, proposed receptors, systemic effects, and translational limitations.

TABLE 4. Pharmacologically underexploited peptides mediating bone–muscle–fat endocrine crosstalk: native peptide biology underdeveloped as therapeutic targets.

The inclusion of myostatin-related signaling fragments highlights an important nuance: biological pathways that appear unattractive when targeted aggressively may yield therapeutic benefit when modulated with greater precision. This principle recurs across underexplored peptide systems and reinforces the importance of dose, context, and pathway selectivity.

From a discovery standpoint, bone–muscle–fat peptides challenge reductionist models of endocrinology by emphasizing network-level regulation (Whitham and Febbraio, 2016). Their effects often emerge only in specific physiological contexts, such as exercise, growth, or aging, and may depend on coordinated signaling across multiple tissues. As drug discovery increasingly embraces systems pharmacology and multidimensional endpoints, these peptides may prove particularly well suited to next-generation therapeutic strategies.

The following section extends this integrative perspective to neuroendocrine and immune–metabolic peptide systems, where complexity has similarly constrained translation despite compelling biological rationale.

7 Neuroendocrine and immune–metabolic peptide systems: complexity as opportunity rather than liability

Neuroendocrine and immune-modulating peptide systems occupy a paradoxical position in drug discovery. On the one hand, they regulate some of the most conserved and powerful physiological processes in humans, including stress adaptation, reproduction, inflammation, autonomic control, and tissue repair. On the other hand, their pleiotropic actions, frequent involvement of the central nervous system, and context-dependent effects have historically rendered them unattractive as therapeutic targets. As a result, many such peptides remain underexplored despite extensive biological validation.

The success of GLP-1 receptor agonists—therapies that exert both central and peripheral effects—has forced a re-evaluation of this cautionary stance. Rather than viewing complexity as an inherent liability, contemporary pharmacology increasingly recognizes that pleiotropic signaling can be therapeutically advantageous when appropriately modulated through dosing, bias, and patient stratification (Kenakin, 2019; Drucker, 2018). This shift is particularly relevant for neuroendocrine and immune–metabolic peptides, whose physiological roles inherently span multiple organ systems.

7.1 Phoenixin: integrating metabolism, reproduction, and affect

Phoenixin is a relatively recently described neuropeptide identified through bioinformatic analysis of conserved peptide sequences and expressed in both central and peripheral tissues. Initial studies demonstrated that phoenixin stimulates gonadotropin-releasing hormone–dependent luteinizing hormone secretion, implicating it in reproductive regulation (Yosten et al., 2013). Subsequent work expanded its functional repertoire to include modulation of anxiety-like behavior, food intake, and metabolic homeostasis.

Phoenixin signals primarily through the G protein–coupled receptor GPR173, although aspects of its signaling biology remain incompletely defined. Of particular interest is the apparent sexual dimorphism observed in several phoenixin-mediated effects, which has complicated translational interpretation. Sexual dimorphism in phoenixin effects has been documented in rodent models by Yosten et al. (2013) and further characterized in the context of anxiety and food intake by Ding et al. (2019), with female animals generally showing stronger phoenixin-mediated responses in reproductive and anxiety paradigms. Historically, sex-specific signaling was often treated as a confounder to be avoided. However, increasing recognition of sex differences in metabolic and neuroendocrine disease suggests that such dimorphism may represent a therapeutic opportunity rather than a barrier.

From a translational perspective, phoenixin exemplifies a class of peptides whose underexplored status reflects conservatism in trial design rather than a lack of biological plausibility. Its involvement at the intersection of metabolic regulation, stress responsiveness, and reproductive endocrinology positions it as a candidate for conditions in which these domains converge, such as menopause-associated metabolic dysfunction or stress-related eating disorders. Careful patient stratification and sex-aware trial designs would be essential for evaluating such applications.

7.2 Relaxin-3 and the behavioral dimension of metabolic disease

Relaxin-3, a member of the relaxin peptide family predominantly expressed in the nucleus incertus, signals through the RXFP3 receptor and exerts pronounced effects on feeding behavior, arousal, stress responsiveness, and cognitive processing in animal models (Smith et al., 2014). Unlike classical satiety peptides, relaxin-3 is orexigenic, stimulating food intake under certain conditions.

At first glance, this profile appears incompatible with obesity therapy. However, relaxin-3 biology highlights a critical but often underappreciated dimension of metabolic disease: the role of stress, affective state, and behavioral context in driving feeding behavior. Obesity, binge eating, and metabolic syndrome frequently coexist with anxiety, depression, and chronic stress, yet most metabolic therapies target peripheral pathways while neglecting central drivers of behavior.

Historically, centrally acting peptides were avoided due to concerns about neuropsychiatric side effects and blood–brain barrier delivery. Advances in biased agonism, region-selective targeting, and peripherally restricted analogs now offer potential strategies for selectively modulating central peptide systems without broad CNS disruption. Relaxin-3 therefore represents a system whose perceived liabilities may mask therapeutic relevance for specific behavioral phenotypes rather than generalized metabolic indications.

7.3 Thymosin-β4: regeneration, repair, and immune–metabolic crosstalk

Thymosin-β4 is a small actin-binding peptide originally isolated from thymic tissue and subsequently shown to promote angiogenesis, reduce inflammation, and enhance wound healing across multiple preclinical models (Goldstein et al., 2012). Unlike many classical peptide hormones, thymosin-β4 does not signal through a well-defined GPCR or receptor tyrosine kinase; instead, it exerts its effects through intracellular interactions and modulation of cytoskeletal dynamics.

The absence of a canonical receptor has complicated traditional drug development approaches, which often rely on receptor binding and structure–activity optimization. Nevertheless, thymosin-β4 has advanced into clinical studies for cardiac repair and corneal wound healing, demonstrating that non-classical signaling peptides can be developed therapeutically when endpoints are well defined.

In the context of metabolic disease, thymosin-β4 is of interest due to the growing recognition that chronic low-grade inflammation and impaired tissue repair contribute to insulin resistance, cardiovascular disease, and aging. Its underexploitation in metabolic indications likely reflects disciplinary silos rather than a lack of biological relevance. However, its angiogenic properties raise legitimate safety considerations, suggesting that indication-specific development—favoring acute or localized applications—may be more appropriate than chronic systemic exposure.

7.4 Catestatin and autonomic–metabolic regulation

Catestatin, a peptide derived from the prohormone chromogranin A, inhibits catecholamine release and modulates sympathetic tone. In preclinical models, catestatin exhibits anti-inflammatory, antihypertensive, and metabolic effects, and reduced circulating levels have been associated with hypertension, obesity, and insulin resistance (Mahata et al., 1997).

Despite these associations, catestatin has received limited attention as a therapeutic candidate, in part because it does not conform neatly to classical endocrine paradigms and lacks a single dominant receptor target. From a translational standpoint, catestatin may be more tractable as a pathway biomarker or as a guide for targeting autonomic dysregulation rather than as a direct peptide therapeutic.

This example underscores a broader point: not all underexplored peptides need to become drugs to influence drug discovery. Some may function best as biological signposts that identify dysregulated systems amenable to pharmacologic intervention through other modalities.

7.5 Safety, sex-specificity, and CNS considerations

Neuroendocrine and immune–metabolic peptides raise distinct safety considerations that must be addressed explicitly. Central nervous system engagement introduces risks of mood alteration, cognitive effects, and behavioral changes, necessitating careful dose titration and patient monitoring. Sex-specific signaling, while potentially advantageous, complicates trial design and regulatory evaluation. Immune-modulating peptides may influence angiogenesis, fibrosis, or tumor biology, requiring indication-specific risk assessment.

These challenges are not unique to peptides and increasingly characterize modern therapeutics across oncology, neurology, and immunology. The appropriate response is not avoidance, but disciplined translational design that aligns mechanism, indication, and risk tolerance.

7.6 Reframing complexity as translational opportunity

Collectively, the neuroendocrine and immune–metabolic peptide systems reviewed in this section challenge the assumption that therapeutic targets must be narrowly defined, peripherally restricted, and mechanistically simple. Instead, they suggest that future advances in peptide therapeutics may arise from embracing biological complexity, provided it is approached with appropriate pharmacologic tools and conceptual frameworks.

The historical tendency to equate pleiotropy with risk rather than opportunity appears increasingly outdated in light of contemporary successes with multi-agonist and network-based therapies. As the field moves toward integrative disease models and precision medicine, neuroendocrine and immune–metabolic peptides may represent a critical frontier for therapeutic innovation.

The final sections of this review synthesize these insights into a strategic framework for distinguishing between failed biology and failed pharmacology, and outline regulatory, commercial, and practical considerations for advancing underexplored peptide–receptor systems toward clinical translation.

8 Regulatory, commercial, and practical considerations in advancing underexplored peptide systems

Scientific plausibility alone is insufficient to advance underexplored peptide–receptor systems into approved therapeutics. Regulatory expectations, manufacturing feasibility, clinical trial design, and commercial differentiation play decisive roles in determining whether a biologically compelling peptide ultimately reaches patients. Importantly, many peptide programs historically failed not because they were scientifically unsound, but because they were misaligned with regulatory frameworks, economic realities, or the prevailing standards of evidence at the time of evaluation. Specific examples include: (1) pramlintide (amylin analog), which received FDA approval only after evidence standards shifted to accommodate an injectable adjunct therapy, having initially faced barriers related to delivery format and market positioning; (2) calcitonin-derived peptides for osteoporosis, which were sidelined in some markets due to evolving risk-benefit standards rather than loss of biological efficacy; and (3) early oxyntomodulin analogs, which were discontinued in part because regulatory endpoints for combination receptor agonism had not yet been established (Weyer et al., 2001; Finan et al., 2016).

8.1 Regulatory expectations and evidence standards

Regulatory agencies increasingly emphasize mechanism-anchored development supported by robust pharmacodynamic biomarkers and clinically meaningful endpoints (FDA, 2022; EMA, 2023). Peptide therapeutics are particularly well suited to this paradigm, as their endogenous nature often allows direct linkage between receptor engagement and downstream physiological effects. However, this advantage is contingent upon rigorous demonstration of exposure–response relationships and the avoidance of overgeneralized claims based solely on preclinical data.

A recurring integrity issue in peptide development has been premature extrapolation from animal models to humans. Several underexplored peptide systems discussed in this review—such as osteocalcin, irisin, and METRNL—exhibit strong phenotypes in rodents but variable or context-dependent signals in humans. Regulators increasingly expect explicit acknowledgment of such uncertainty and clear plans to resolve it through biomarker-driven early-phase studies, rather than relying solely on associative epidemiology. Failure to delineate these limitations can undermine regulatory confidence even when the underlying biology is compelling. Importantly, however, many historically transformative drugs were approved without a complete mechanistic understanding or full translational validation prior to human testing. Aspirin, metformin, and numerous early vaccines were developed empirically; their mechanisms were clarified post hoc. What has changed is not the feasibility of developing drugs without complete biological knowledge, but the expectation that developers be transparent about what is and is not known, and that uncertainty be actively managed rather than minimized (ICH E9 guidance; Woodcock and LaVange, 2017). The present regulatory environment thus favors explicit uncertainty mapping, not the elimination of uncertainty as a precondition for development.

8.2 Safety evaluation and long-term risk management

Chronic peptide therapy raises safety considerations that differ in some respects from those of small molecules (Liang et al., 2020). Peptides generally lack reactive metabolites and often degrade into endogenous amino acids, reducing certain toxicological risks. At the same time, sustained receptor engagement may induce adaptive responses such as receptor desensitization, endocrine feedback suppression, or compensatory pathway activation. These effects may not be evident in short-term studies but become clinically relevant with long-term administration. It is important to note that receptor desensitization, feedback suppression, and compensatory signaling are by no means unique to peptides—these phenomena are well documented for small-molecule drugs, including beta-blockers, opioids, and statins. What may distinguish certain peptide therapeutics is the degree of physiological mimicry involved, which can make it harder to predict adaptive homeostatic responses in advance. This distinction argues for careful long-term monitoring in peptide development programs, rather than suggesting that such risks are categorically greater than those of other modalities.

Experience with GLP-1 receptor agonists underscores the importance of contextualizing safety signals rather than interpreting them in isolation. Gastrointestinal adverse effects, initially viewed as limiting, were ultimately managed through dose titration and formulation design. Conversely, rodent-specific tumor findings prompted regulatory warnings that continue to influence labeling despite uncertain relevance to humans. These precedents highlight the need for indication-specific risk assessment and careful differentiation between mechanism-based toxicity and species-specific artifacts.

Underexplored peptide systems with immune or angiogenic activity, such as thymosin-β4, warrant particularly cautious evaluation (Sosne and Kleinman, 2015). While regenerative and anti-inflammatory properties may be therapeutically valuable, they also raise theoretical concerns regarding fibrosis or tumor promotion. Regulatory strategy should therefore prioritize acute or localized indications when appropriate and avoid extrapolation to chronic systemic use without compelling safety data.

8.3 Manufacturing, formulation, and cost of goods

From a commercial perspective, peptide therapeutics face persistent scrutiny regarding manufacturing complexity and cost of goods (Babu et al., 2021). Advances in solid-phase peptide synthesis, recombinant expression, and purification technologies have substantially reduced these barriers, enabling large-scale production of complex peptides with acceptable margins. Nevertheless, underexplored peptides lacking dramatic efficacy advantages may struggle to justify development if manufacturing costs cannot be offset by clinical differentiation.

Long-acting formulations, while therapeutically advantageous, introduce additional complexity in manufacturing and quality control (Maier et al., 2021). Lipidation, conjugation, and fusion strategies must be evaluated not only for pharmacokinetic benefit but also for scalability, stability, and regulatory acceptance. Early integration of chemistry, manufacturing, and controls considerations into translational planning is therefore essential to avoid late-stage attrition.

8.4 Clinical differentiation in a post-GLP-1 landscape

The success of incretin-based therapies has raised expectations for efficacy in metabolic disease, particularly in obesity, where benchmarks for weight loss and cardiometabolic improvement are now well established (Kushner and Kahan, 2024). Underexplored peptide systems may struggle to compete directly with GLP-1-based therapies unless they offer clear advantages, such as improved tolerability, complementary mechanisms, or benefit in patient populations poorly served by existing drugs.

This reality favors development strategies that emphasize differentiation rather than replacement. Peptides that enhance metabolic resilience, preserve lean mass, improve behavioral regulation, or target comorbid conditions may find viable niches even if they do not match the magnitude of weight loss achieved with incretin therapies. Combination approaches—whether through co-administration or unimolecular polypharmacology—are particularly attractive for underexplored peptides whose strengths lie in domains not fully addressed by current standards of care.

8.5 Reimbursement and health technology assessment

Reimbursement considerations increasingly influence drug development strategy from early stages (NICE, 2022). Health technology assessment bodies require demonstration of value beyond statistical efficacy, including durability of effect, quality-of-life improvement, and reduction in downstream healthcare costs. Peptide systems that address multiple disease dimensions—such as metabolic control, functional capacity, and psychological well-being—may be well positioned to meet these criteria, provided that clinical trials are designed to capture these outcomes.

Conversely, peptides developed solely on the basis of biomarker changes without clear clinical relevance may face reimbursement challenges regardless of regulatory approval (Ciani et al., 2023). Alignment between biological mechanism, clinical endpoints, and payer expectations is therefore a critical component of translational success.

8.6 Scientific integrity and responsible framing

From a scientific-integrity standpoint, the renewed interest in underexplored peptide systems carries an obligation to avoid overstated claims and selective citation. Review articles must distinguish clearly between established evidence, emerging hypotheses, and speculative opportunities. Overgeneralization of preclinical findings or uncritical extrapolation from isolated studies risks undermining credibility and impeding constructive discourse.

Throughout this review, emphasis has been placed on transparent acknowledgment of uncertainty, careful grading of evidence, and explicit identification of translational gaps. This approach is not intended to diminish enthusiasm for underexplored peptide systems, but rather to strengthen the case for their systematic and responsible re-evaluation using modern tools.

8.7 Strategic implications for drug discovery

Taken together, regulatory, commercial, and practical considerations suggest that underexplored peptide–receptor systems are best advanced through focused, indication-specific strategies that leverage their unique biological properties rather than forcing them into existing paradigms (Ahrén, 2022; Drucker, 2018). Success will depend on disciplined translational design, early integration of manufacturing and regulatory planning, and a realistic assessment of the competitive landscape.

The final section synthesizes these insights into a decision framework for distinguishing peptide systems that merit renewed investment from those that should remain abandoned and articulates a forward-looking perspective on the future of peptide therapeutics.

9 Distinguishing failed biology from failed pharmacology: a decision framework

A central objective of this review is to distinguish peptide–receptor systems that were abandoned due to intrinsic biological limitations from those that failed primarily because of incomplete pharmacologic execution. This distinction is not merely academic; it has direct implications for resource allocation, translational strategy, and scientific integrity in drug discovery. Conflating failed pharmacology with failed biology risks permanently sidelining therapeutically valuable systems, while indiscriminately resurrecting abandoned targets without rigorous criteria risks repeating historical mistakes.

The decision framework proposed here integrates biological plausibility, translational evidence, safety signals, and technological feasibility. It is intended to guide rational re-evaluation rather than to advocate indiscriminate revival of underexplored peptide systems. This framework is intended as a conceptual guide rather than a deterministic regulatory algorithm.

9.1 Criteria suggesting failed pharmacology rather than failed biology

Several characteristics consistently indicate that a peptide system may have been abandoned prematurely due to pharmacologic or methodological limitations rather than biological inadequacy.

First, failure occurring at supraphysiologic exposure levels is a strong indicator of pharmacologic rather than biological failure. Many early peptide programs relied on acute or high-dose administration, which produced adverse effects unrelated to therapeutic exposure levels. The subsequent success of GLP-1 receptor agonists following dose smoothing and the introduction of long-acting formulations underscores that early toxicity signals may be mitigated through improved pharmacokinetics rather than abandoning the target.

Second, lack of durable exposure or poor temporal alignment between dosing and physiology suggests pharmacologic failure. Peptides with short half-lives were often dismissed because efficacy could not be sustained, even when acute biological effects were robust. Classic examples include native GLP-1, which has a plasma half-life of approximately 2 minutes and required continuous infusion in early studies—an impractical route for chronic therapy—yet was subsequently transformed into a once-weekly therapeutic through lipidation and albumin-binding strategies (Drucker, 2018). Similarly, oxyntomodulin requires multiple daily injections in native form, which precluded commercial development at the time. Advances in half-life extension and controlled-release strategies substantially weaken this rationale for abandonment.

Third, pleiotropic signaling that aligns with physiological function rather than nonspecific toxicity favors re-evaluation. Endogenous peptides frequently evolved to coordinate multiple processes simultaneously. When adverse effects mirror the peptide’s known physiological actions rather than off-target toxicity, the appropriate response may be signal bias or contextual restriction rather than target rejection.

Fourth, incomplete receptor characterization or the absence of subtype-selective tools at the time of evaluation strongly favors failed pharmacology. Several peptide systems were investigated before their receptors were cloned or before structure–function relationships could be interrogated. In such cases, early failure reflects technological immaturity rather than biological irrelevance.

Finally, convergence of evidence across species, genetic models, or independent experimental systems supports biological validity even in the absence of successful early clinical translation. When multiple lines of evidence point in the same physiological direction, negative translational outcomes should be scrutinized for methodological rather than biological causes.

9.2 Criteria suggesting true biological failure

Conversely, certain characteristics indicate that abandonment of a peptide system is likely justified on biological grounds.

The most definitive indicator is consistent on-target toxicity at therapeutically relevant exposure levels. When adverse effects occur within the same exposure range required for efficacy and cannot be mitigated through dosing, formulation, or pathway bias, biological failure is likely.

Second, repeated failures in well-designed human studies, despite adequate exposure and appropriate endpoints, suggest that preclinical models may not translate meaningfully into human physiology. In such cases, further investment may be difficult to justify without new mechanistic insights.

Third, essential physiological functions that cannot be selectively modulated without unacceptable disruption favor abandonment. Peptides that regulate fundamental homeostatic processes—such as core cardiovascular or respiratory control—may be unsuitable as chronic therapeutics if selective modulation proves infeasible.

Fourth, the absence of corroborating human genetic or observational evidence weakens the case for continued development, particularly when coupled with marginal preclinical effects. While a lack of genetic association does not exclude therapeutic potential, it lowers confidence when other indicators are weak. It is important, however, to maintain a balanced perspective: many highly successful drugs were developed without prior human genetic validation. Statins, ACE inhibitors, and the majority of cancer chemotherapies were advanced through pharmacologic and clinical reasoning rather than Mendelian genetics. Genetic validation increases confidence in target biology but should be viewed as a supportive criterion rather than a prerequisite; its absence is informative but not disqualifying, especially when mechanistic and physiological evidence is otherwise robust (Nelson et al., 2015).

Finally, insurmountable technical barriers—such as inability to manufacture stable formulations, extreme immunogenicity, or lack of feasible delivery routes—may justify abandonment independent of biological plausibility.

9.3 Application of the framework to peptide systems reviewed herein

Applying this framework to the peptide systems discussed in this review clarifies their translational status.

Apelin exhibits strong metabolic and cardiovascular biology, with failure driven largely by exposure-related hemodynamic effects and lack of signaling bias, suggesting failed pharmacology rather than failed biology. Oxyntomodulin similarly reflects premature abandonment due to concerns about dual-receptor activity that have since been addressed by modern polypharmacologic approaches.

Peptide YY and other satiety peptides demonstrate clear physiological roles, with early failures attributable to rapid exposure and intolerance rather than to a lack of efficacy, again favoring re-evaluation. In contrast, peptides whose human effects remain weak or inconsistent despite adequate exposure may warrant lower priority absent new mechanistic insights.

Osteocalcin and irisin occupy an intermediate category, where strong preclinical biology contrasts with heterogeneous human data. Here, the framework suggests cautious re-evaluation focused on assay standardization, context-specific endpoints, and direct pharmacologic modulation rather than continued reliance on observational correlations.

Neuroendocrine peptides such as relaxin-3 and phoenixin highlight the importance of indication alignment. Their biological effects may be inappropriate for generalized metabolic disease but highly relevant for behaviorally mediated subtypes, reinforcing the need for stratified translational strategies.

9.4 Strategic value of a structured decision framework

Beyond individual targets, adopting a structured decision framework has broader implications for scientific integrity. It promotes transparency in how targets are prioritized, discourages selective citation or post hoc rationalization, and reduces the risk of repeating historical cycles of enthusiasm and abandonment. For review articles in particular, explicit articulation of decision criteria strengthens credibility by demonstrating that inclusion reflects systematic reasoning rather than narrative convenience.

The final section of this review synthesizes these insights into a forward-looking perspective on the future of peptide therapeutics and articulates why the rediscovery of dormant biology, when guided by modern pharmacologic principles, may represent the most productive frontier in drug discovery.

10 Synthesis and future outlook: rediscovering dormant biology in the era of peptide engineering

The cumulative evidence reviewed across metabolic, appetite-regulatory, bone–muscle–fat, neuroendocrine, and immune–metabolic peptide systems support a unifying conclusion: the apparent scarcity of transformative peptide therapeutics is not a consequence of limited biological opportunity, but rather of historical constraints in pharmacologic execution, translational strategy, and conceptual framing. The success of GLP-1 receptor agonists has not revealed new principles of endocrinology; instead, it has exposed how many endogenous peptide systems were evaluated prematurely, using tools and assumptions that no longer reflect the state of the field.

A recurring theme throughout this review is that peptide systems were often abandoned at precisely the stage where modern technologies now exert their greatest leverage. Short half-life, pleiotropy, and behavioral or cardiovascular effects were historically interpreted as disqualifying features. In retrospect, these characteristics frequently reflect the physiological roles peptides evolved to perform. The clinical maturation of GLP-1 receptor agonists demonstrates that such features can be reshaped through long-acting formulations, exposure smoothing, biased agonism, and indication-specific dosing rather than being avoided altogether.

Equally important is the recognition that not all abandoned peptide systems merit resurrection. This review has deliberately distinguished failed biology from failed pharmacology, emphasizing that genuine on-target toxicity, repeated lack of efficacy in well-designed human studies, or insurmountable technical barriers justify abandonment. Scientific integrity demands that enthusiasm for rediscovery be tempered by disciplined evaluation. The decision framework articulated herein provides a structured approach to this problem, replacing narrative optimism with transparent criteria.

From a discovery perspective, underexplored peptide–receptor systems offer several strategic advantages. They are grounded in endogenous biology, often supported by convergent evidence across species and experimental modalities, and frequently act at integrative nodes that coordinate multiple physiological processes. In an era increasingly defined by complex, multifactorial diseases, such systems may be better suited to therapeutic intervention than narrowly targeted pathways optimized for reductionist endpoints.

The implications extend beyond individual peptide candidates. Advances in peptide chemistry, receptor pharmacology, and systems biology have effectively shifted the reference standard for translational success. Measurement has become definition, variability has become signal, and complexity has become a source of competitive advantage rather than a liability. This shift mirrors historical inflection points in other scientific domains, where progress accelerated not through incremental refinement, but through redefinition of the underlying framework.

Looking forward, the most impactful advances in peptide therapeutics are likely to emerge from the systematic re-examination of known biology rather than from the discovery of entirely new hormones (Drucker, 2020). Endogenous peptides that were once sidelined due to incomplete tools or conservative assumptions may now represent better-de-risked opportunities than entirely novel targets. Success will depend on aligning biological insight with modern pharmacologic design, realistic regulatory strategies, and clinically meaningful endpoints.

In conclusion, underexplored peptide–receptor systems constitute a vast and largely untapped reservoir of therapeutic potential. Their neglect reflects historical limitations rather than biological inadequacy. When approached with rigor, transparency, and contemporary translational tools, the rediscovery of dormant peptide biology may define the next frontier of drug discovery. Future advances in structural biology, computational modeling, peptide engineering, and patient stratification are expected to accelerate systematic exploitation of genetically validated peptide targets, converting biological promise into clinical reality (Fosgerau and Hoffmann, 2015; Drucker, 2020).

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Footnotes

Edited by: Liang Xu, University of Kansas, United States

Reviewed by: Christel Menet, Confo Therapeutics, Belgium

Anukriti Saran, Banasthali University, India