Jul 2026· Journal of Medicinal Chemistry· Vol 69, pp. 17770 - 17799· 0 citations· 160 references
Medicine
TL;DR
This report analyzes trends in cyclic peptide research using data from the CAS Content Collection over the past two decades to provide a comprehensive view of the evolving cyclic peptide landscape and emerging principles guiding their future development.
Abstract
Peptide therapeutics are an important drug modality due to their high specificity, favorable safety, and expanding design potential. Among them, cyclic peptides occupy a space between small molecules and biologics, offering improved rigidity, stability, and target engagement. This report analyzes trends in cyclic peptide research using data from the CAS Content Collection over the past two decades. Results show a steady rise in academic publications and patents, reflecting growing interest across discovery and development. Notably, oral administration is gaining attention, indicating progress toward addressing long-standing bioavailability challenges. Beyond delivery, we examine how peptide and cyclization types, along with specific chemical modifications, relate to administration routes, therapeutic indications, and molecular targets. We also assess physicochemical properties to understand how molecular features influence developability. Together, these insights provide a comprehensive view of the evolving cyclic peptide landscape and emerging principles guiding their future development.
Peptide-based therapeutics have become a flexible type of medicine that combines high target specificity and strong biological activity with good safety profiles. They effectively connect small-molecule drugs and biologics. Since insulin was first used in 1922, more than 100 peptide drugs have been approved around the world, and their use is growing in diabetes, cancer, rare diseases, and autoimmune disorders. However, their clinical use is still limited by rapid enzymatic degradation, short half-life, poor membrane permeability, low oral bioavailability, and formulation instability. This review presents a unified innovation framework that integrates upstream molecular engineering strategies including cyclization, peptide stapling, D- and β-amino acid substitution, PEGylation, and backbone modification with downstream advanced delivery platforms such as nanocarriers, microneedles, self-assembling hydrogels, and stimuli-responsive systems, while also addressing critical translational considerations including scalability, regulatory requirements, and manufacturing consistency. By critically linking structural modifications at the molecular level with formulation performance and clinical translation factors, and by evaluating both approved products and persistent gaps in predictive modelling and patient-centric delivery, this work offers practical insights that go beyond the scope of most existing reviews. The integrated perspective presented here highlights how these combined approaches are shifting peptide therapeutics from conventional injectable formats toward more stable, convenient, and precisely targeted solutions, paving the way for the next generation of patient-friendly peptide medicines.
Pradip Karale, Saloni Borse, Anjali Gavit et al.· Journal of Pharmaceutical In...· 0 citations
Since its introduction in 1951, bioisosterism has become a cornerstone strategy in drug design and development, enabling chemists to rationally modify molecular structures to optimize biological and physicochemical properties. In this perspective, we examine 57 FDA-approved drugs and 18 advanced drug candidates wherein bioisosteric replacements were successfully employed to address a range of developability challenges encountered during lead optimization. These strategic substitutions have led to significant improvements in potency, selectivity, solubility, and metabolic stability, while simultaneously mitigating issues related to lipophilicity, plasma protein binding, and the formation of reactive metabolites. Together, these examples highlight the enduring impact of bioisosterism as a versatile tool for fine-tuning drug candidates and overcoming the multifaceted challenges of modern medicinal chemistry.
Yong-Jin Wu, Alyah F. Chmiel, Joanne J. Bronson· Journal of Medicinal Chemist...· 1 citation
Natural cyclic peptides have long served as a rich reservoir of bioactivity, occupying a unique region of the drug space that bridges the gap between small molecules and large biologics. Evolution has perfected the macrocyclic architecture to achieve exceptional target specificity and metabolic stability, providing a structural blueprint that allows these molecules to engage extended protein surfaces often inaccessible to conventional drugs. While early landmarks like cyclosporin A demonstrated the power of chameleonicity, the ability to adapt conformations to different environments - the field is currently undergoing a paradigm shift. Nature is no longer viewed merely as a source of lead compounds to be mined, but as a conceptual framework for de novo design. By integrating natural principles such as conformational constraint and amide-masking with cutting-edge technologies like mRNA display (e.g. RaPID) and artificial intelligence, researchers are now rationally engineering next-generation macrocycles, positioning them at the frontier of modern drug development.
Greta Bergamaschi, Giulia Lodigiani, Stefano Gandolfi et al.· Current Opinion in Chemical...· 0 citations
Covalent inhibitors have re-emerged as a powerful class of therapeutics due to their prolonged target engagement, ability to decouple pharmacokinetic availability from pharmacodynamic outcome, potential for high selectivity and ability to modulate traditionally 'undruggable' targets. Historically, cysteine residues have dominated covalent drug discovery owing to their unique nucleophilicity and relative scarcity in the proteome. However, the desire to broaden the chemical scope of covalent therapeutics has driven a surge of interest in irreversibly targeting other amino acid residues, such as lysine, serine, tyrosine, threonine and histidine. This review explores the outstanding questions and challenges in developing covalent inhibitors beyond cysteine, highlighting current warhead chemistries, strategies for achieving selectivity, proteomic mapping advances, assessment of the intrinsic reactivity of the electrophiles targeting non-cysteine residues and opportunities for expanding the druggable proteome. We also discuss future directions and the pharmacological implications of non-cysteine covalent modifications in therapeutic contexts.
B. Srinivasan, John B Taylor· British Journal of Pharmacol...· 0 citations
Click chemistry has fundamentally transformed modern medicinal chemistry by providing a versatile, high-yielding, and chemoselective strategy for assembling complex molecular architectures under mild reaction conditions. Since its introduction, this synthetic approach has become an indispensable tool for the rapid construction of biologically active molecules, particularly in peptide-based drug discovery, where structural precision, metabolic stability, and synthetic efficiency are critical determinants of therapeutic success. Among the various click reactions, copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC) has gained widespread recognition because of its exceptional regioselectivity, functional-group tolerance, and ability to generate stable 1,2,3-triazole linkages that effectively mimic peptide and amide bonds. These attributes have significantly expanded opportunities for developing peptide therapeutics with improved pharmacological performance and enhanced resistance to enzymatic degradation. This review critically examines the scientific evolution of click chemistry and its expanding role in peptide engineering, drug design, and pharmaceutical innovation. Particular emphasis is placed on the mechanistic basis of major click reactions, triazole-mediated peptide modification, peptide cyclization, stapling strategies, and the development of therapeutics for cancer, infectious diseases, inflammatory disorders, and other clinically significant conditions. Recent advances in bio-orthogonal chemistry, targeted drug delivery, molecular imaging, Nano medicine, and bio molecular conjugation are also discussed to illustrate the broad translational impact of click chemistry across contemporary biomedical research. In addition, the review highlights the emerging convergence of click chemistry with artificial intelligence, machine learning, and computational drug discovery, emphasizing how predictive molecular design, reaction optimization, and virtual screening are reshaping medicinal chemistry workflows. Current limitations, including catalyst-associated toxicity, scalability, manufacturing challenges, and regulatory considerations, are critically evaluated alongside promising solutions that support sustainable and clinically translatable pharmaceutical development. By integrating foundational concepts with recent scientific advances, this review provides a comprehensive perspective on the present status of click chemistry and outlines future directions for its application in peptide therapeutics, precision medicine, and next-generation drug discovery.
M. Gorikapudi, K. S. K. Kumar· Indian Journal of Pharmaceut...· 0 citations
This manuscript traces my journey through computational medicinal chemistry, showing how mechanistic and structural insights and physicochemical reasoning enable the translation of challenging targets into drugs and general design principles. The central theme, conformational analysis, links on-target potency via pre-organization of the bioactive conformation with physics-based physicochemical property prediction. This strategy can unlock dramatic gains in lipophilic efficiency and pharmacokinetic properties through the judicious addition of single atoms. This principle is extended to proteins, particularly kinases, where discrete conformational states can explain binding modes and kinetics. Binding to inactive conformations is linked to slow-on/ slow-off kinetics and can be engineered through ligand design or protein mutations. The manuscript summarizes principles of oral bioavailability in beyond-Rule-of-5 (bRo5) space, highlighting neutral polarity as a key determinant of permeability and exposure. Marketed oral bRo5 drugs and the lead optimization campaigns of first in class representatives converge on a polarity-lipophilicity sweet spot. Finally, nonclassical zwitterions represent a general design strategy to reconcile low lipophilicity with high permeability, supported by strong agreement between computation and experiment.
