Aug 2026· Current Opinion in Chemical Biology· Vol 94, pp.
102738
· 0 citations· 67 references
Medicine
TL;DR
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, and researchers are rationally engineering next-generation macrocycles, positioning them at the frontier of modern drug development.
Abstract
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.
N-methylated macrocyclic peptides hold a unique position in modern drug discovery, owing to their superior affinity, specificity, and safety compared to small-molecule drugs, as well as their favorable physicochemical properties, faster distribution and generally lower immunogenicity compared to antibody drugs. As with all synthetic drug modalities, an efficient preparation method is a prerequisite for the drug discovery process based on this molecular format. However, the chemical synthesis of N-methylated macrocyclic peptides was a persistent challenge until very recent breakthroughs, mostly driven by the difficulties of assembling the multiple N-methylated linear precursors. This review focuses on two key aspects involving the generation of such peptides, aiming to provide practical guidance to peers sharing the same interest: the strategies of peptide cyclization and the chemistries of assembling sterically hindered linear precursors.
Xuchun Zhang, Yishan Guo, Fa Liu et al.· Chemical Communications· 0 citations
Macrocyclic peptides are attracting attention as a promising therapeutic modality for addressing intracellular targets that are traditionally difficult to address with conventional small molecules or antibodies. In this study, we present the chemical optimization process behind the development of AUBE00 (AP7400, compound 30), a KRAS-selective inhibitor based on a scaffold similar to LUNA18, an orally bioavailable macrocyclic peptide RAS inhibitor. Achieving KRAS isoform selectivity is exceptionally challenging due to the nearly identical backbone structures of KRAS, HRAS, and NRAS (Cα RMSD < 1.1 Å). The success of this study relied on two critical factors: (1) achieving conformational control of the flexible N-alkyl group through a bridging structure linked to the adjacent side chain, which enabled the exploitation of subtle interaction energy differences among the isoforms; and (2) overcoming the trade-off between improved KRAS selectivity and reduced permeability associated with P-glycoprotein (P-gp) substrate liability by employing a modified Caco-2 membrane permeability assay to recover oral bioavailability. Our results demonstrate that a conformational rigidification through a bridged scaffold, implemented while preserving membrane permeability, is a highly effective strategy for achieving isoform selectivity. This study establishes a generalizable design principle for orally bioavailable macrocyclic peptides targeting intracellular proteins that require mutation or isoform selectivity.
M. Kage, Hatsuo Kawada, Koji Takano et al.· Journal of the American Chem...· 0 citations
Peptidomimetics have matured from motif‑based inhibitors into a structural engineering discipline that systematically translates peptide recognition surfaces into drug‑like scaffolds. Driven by the urgent clinical demand to overcome the inherent pharmacological liabilities of biomolecules, the field is undergoing a decisive Peptide-to-Small Molecule paradigm shift-functionally converting peptide-derived recognition motifs into orally bioavailable synthetic therapeutics. This Perspective highlights how foundational geometric design principles-linear repetition, convergent fusion, and cyclization-define next‑generation architectures capable of targeting complex protein-protein interactions (PPIs). Repeating‑unit oligomers exemplify linear projection strategies, heterocycle‑centered scaffolds embody the convergent fusion of recognition motifs, and macrocyclic frameworks pre-organize bioactive conformations while enabling access to non‑canonical topologies. Beyond simple mimicry, these architectures increasingly embrace dynamic responsiveness, aggregation remodeling, and universal multi‑structure platforms. We argue that the convergence of geometric logic with automated synthesis and AI‑driven design will transform peptidomimetics into a primary modality for decoding and therapeutically engaging the human interactome, including historically "undruggable" PPIs.
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.
T. Thite, Kavita A. Iyer, Preeti Jain et al.· Journal of Medicinal Chemist...· 0 citations
The central theme, conformational analysis, links on-target potency via pre-organization of the bioactive conformation with physics-based physicochemical property prediction with physics-based physicochemical property prediction, highlighting neutral polarity as a key determinant of permeability and exposure.
Heterocyclic scaffolds are vital to medicinal chemistry due to their versatility, diversity, and ability to target various biological molecules. This review covers advances in designing and synthesizing bioactive heterocycles, highlighting structure-based drug design (SBDD) and ligand-based drug design (LBDD) approaches with computational modeling and Artificial Intelligence (AI) to find potent, selective molecules with good Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) profiles. Case studies show the successful development of heterocyclic drugs for cancer, microbial infections, inflammation, viral infections, and Central Nervous System (CNS) disorders. Synthetic methods have evolved from classical electrophilic/nucleophilic reactions to modern techniques like multicomponent reactions, microwave synthesis, metal catalysis, and green chemistry, making frameworks more accessible. The review discusses Quantitative Structure-Activity Relationship (QSAR) studies for molecular optimization. Challenges like synthetic complexity and resistance remain, but emerging trends like machine learning, omics, and enzyme synthesis offer new opportunities. Ultimately, combining design principles and innovative methods can speed up drug discovery and enable sustainable, personalized therapies with heterocyclic pharmacophores.
Debajit Dewan, Bhupender Nehra, R. Nath et al.· Future Medicinal Chemistry· 0 citations
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