Cyclic Peptides in Drug Discovery: What a Decade of CAS Data Tells Us
A recent J. Med. Chem. perspective by @[Trupti Thite](urn:li:person:CRIuJl1wqq) analysed close to 46,000 cyclic peptides indexed in the CAS Content Collection between 2020 and 2025, and the resulting picture of the field is a useful one for anyone tracking where peptide-based drug discovery is heading. Journal output and patent filings have both grown steadily since 2015, with patents overtaking journal articles in 2023 and 2024, a shift the authors read as a move toward commercialisation rather than pure discovery. Macrocyclic and bicyclic architectures dominate the therapeutically relevant chemical space, and head to tail cyclisation remains the preferred strategy, prized for its reliability in conferring protease resistance without adding synthetic complexity. Oncology continues to account for the largest share of therapeutic interest, followed by infectious, inflammatory, autoimmune, cardiovascular, metabolic and neurodegenerative indications. One section of the paper stands out: the strategies used to improve oral bioavailability, still one of the field's most persistent limitations. Most cyclic peptides sit well outside Lipinski and Veber space, with the analysis finding that the majority breach four or five classical rules at once. The authors instead highlight how specific chemical modifications are used to work around this. Backbone N-methylation was the most prevalent modification identified across the dataset, reducing hydrogen bond donor count and masking polarity to improve passive membrane permeation, and it shows strong co-occurrence with oral, rectal and intravenous routes of administration. Incorporation of noncanonical residues, including D-amino acids and β-amino acids, is reported to extend proteolytic stability alongside these permeability gains. A related and less appreciated approach, amide to ester substitution, has been shown in recent work to improve membrane permeability of model cyclic peptides while avoiding some of the metabolic liabilities associated with heavy N-methylation, offering an alternative route to the same design goal. Separately, a combinatorial synthesis and screening approach built on thioether cyclisation and iterative acylation recently delivered a cyclic peptide thrombin inhibitor with oral bioavailability of up to 18 percent in rats, a result the authors describe as a promising general strategy for generating orally available peptide candidates. Together these findings reinforce that oral bioavailability in this modality is being pursued through careful, cumulative property tuning rather than any single fix, with N-methylated and noncanonical amino acid building blocks sitting at the centre of that toolkit. Explore our range of amino acids at https://lnkd.in/eVbfw6Ua Cyclic Peptides in Modern Drug Discovery: Trends and Therapeutic Directions https://lnkd.in/eCZtGjfN
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