Nucleic Acid-Targeting Polyamides: Programmable Recognition and Therapeutic Regulation of DNA and RNA

Modulating gene expression by directly targeting the genome and transcriptome remains a transformative frontier in molecular medicine. While conventional small molecules primarily target protein pockets and oligonucleotide therapeutics face significant cellular delivery and metabolic stability hurdles, nucleic acid-targeting polyamides occupy a distinctive middle-molecule therapeutic space. Synthetic polyamides, most notably pyrrole-imidazole oligomers that read the minor groove of double-stranded DNA and peptide nucleic acids (PNAs) that hybridize with high-affinity RNA and DNA sequences, offer programmable, sequence-specific regulation without requiring complex carrier formulations. Recent advances have revitalized this field, transitioning polyamides from basic molecular probes into potent therapeutic leads. Breakthroughs in chemical modifications, epigenetic conjugates, transcription-factor displacement, and strand-invading genomic repair platforms now enable the direct targeting of historically "undruggable" oncogenes, persistent viral genomes, and fibrotic pathways. This resurgence underscores the critical need to unify chemical biology, structural engineering, and preclinical pharmacology.This Research Topic aims to provide a comprehensive, state-of-the-art overview of nucleic acid-targeting polyamides as next-generation therapeutic modalities. By bridging rational molecular design, chemical synthesis, and translational pharmacology, we seek to highlight innovative strategies that overcome long-standing hurdles, such as pharmacokinetic optimization, off-target binding, and chemical scalability. We invite original research articles and authoritative reviews focusing on novel minor groove binders, modified PNA chemistries, sequence-specific alkylators, and polyamide-based epigenetic or targeted degradation chimeras. Contributions demonstrating in vivo therapeutic efficacy across various disorders caused by genetic mutations or viral infections are particularly encouraged. Ultimately, this collection intends to establish a collaborative benchmark for academia and the biopharmaceutical industry, elucidating how precision synthetic polyamides can expand the targetable genome and transcriptome, thereby accelerating their journey from chemical discovery to clinical reality.This Research Topic integrates current knowledge and opinions on nucleic acid-targeting polyamides in relation to programmable recognition and therapeutic regulation of DNA and RNA. We are interested in original research, systematic reviews, methods, reviews, mini-reviews, hypotheses and theory, perspectives, and brief research reports that fit within the scope of the Research Topic. Themes to be covered in this research topic may include, but are not limited to:• Innovative Chemistry: Novel minor groove binders (such as pyrrole-imidazole oligomers), modified PNAs, sequence-specific alkylators, and polyamide-based epigenetic or targeted degradation chimeras.• Pharmacology & Delivery: Strategies for overcoming hurdles in pharmacokinetic optimization, cellular delivery, off-target binding, metabolic stability, and chemical scalability.• Therapeutic Applications: Advancements in transcription-factor displacement, strand-invading genomic repair, and in vivo efficacy in various intractable diseases. Topic editors: Yuhei Nishimura, Hiroshi Sugiyama Source: https://www.frontiersin.org/research-topics/86547/nucleic-acid-targeting-polyamides-programmable-recognition-and-therapeutic-regulation-of-dna-and-rna