The Role of Glycosylation in Revolutionizing Peptide and Protein Therapeutics

Glycosylation is one of the most ubiquitous post-translational modifications observed in peptides and proteins. It influences the structural and functional properties of these macromolecules, thereby profoundly affecting numerous biological processes. Despite recent advances in understanding the functional importance of O-glycans, clinical translational glycoengineering has predominantly focused on N-glycans. To harness the beneficial characteristics of glycans, strategies involving the attachment of N-glycans to peptides, proteins, nucleic acids, and other molecules have proven effective in engineering therapeutic drugs that improve solubility and pharmacokinetic properties compared to the original molecules, while simultaneously reducing biodegradability, aggregation, and immunogenicity. Furthermore, these drugs can be targeted to specific tissues and organs depending on their glycan structures and patterns. To ensure the safety and therapeutic efficacy of glycosylated compounds, it is essential to site-specifically attach a uniform glycan structure to the target compound while conducting thorough glycan structural analysis. From this perspective, chemical approaches represent one of the most reliable strategies to meet this requirement. In addition to the chemical synthesis of Asn(glycan)-containing peptides and proteins, chemoselective glycosylation methods that can be performed in aqueous solution as a post-synthesis step are also available.A comprehensive examination of the relationship between glycan structures and the biological functions of peptides, proteins, antibodies, and other molecules is essential to enhance our understanding of how glycosylation influences biological processes involving these molecules. This knowledge is expected to contribute to the development of effective treatments and disease prevention strategies. Recent advances in glycoengineering, analytical technologies, and manufacturing strategies have significantly expanded opportunities for the rational design and optimization of next-generation biopharmaceuticals. Consequently, it is essential to assess the current landscape of synthesis and analytical approaches for glycopeptide and glycoprotein therapeutics, identify existing challenges and areas in need of further innovation, and delineate prospective directions for future research and development.• Fundamental roles of glycosylation in peptide and protein therapeutics • Regulation of efficacy, safety, and stability through glycan modifications • Highly reliable and efficient glycopeptide synthesis methods • Chemical and enzymatic ligation techniques • Chemical synthesis and semi-synthesis methods of glycans • Glycan extraction from natural products and glycan remodeling via chemical and/or enzymatic reactions • NMR and other analytical methods for confirming glycan structures • Latest trends in glycoengineering and synthetic biology approaches • Challenges and solutions in methodologies for verifying glycosylation sites and glycan structural homogeneity in manufacturing processes and quality control • Prospects for chemical-based translational strategies and the development of next-generation Topic editors: Yuji Nishiuchi, M. Akhter Hossain, Ryo Okamoto Source: https://www.frontiersin.org/research-topics/82131/the-role-of-glycosylation-in-revolutionizing-peptide-and-protein-therapeutics