Triscysteine disulfide-directing motifs enabling design and discovery of multicyclic peptide binders.

Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE

Original Publication: [London] : Nature Pub. Group

Disulfides*/chemistry ; Cysteine*/chemistry ; Peptide Library*; Amino Acid Motifs ; Drug Discovery/methods ; Amino Acid Sequence ; Peptides/chemistry ; Peptides/metabolism ; Peptides, Cyclic/chemistry ; Peptides, Cyclic/metabolism ; Protein Binding ; Humans ; Oxidation-Reduction ; Protein Folding

Peptides are valuable for therapeutic development, with multicyclic peptides showing promise in mimicking antigen-binding potency of antibodies. However, our capability to engineer multicyclic peptide scaffolds, particularly for the construction of large combinatorial libraries, is still limited. Here, we study the interplay of disulfide pairing between three biscysteine motifs, and designed a range of triscysteine motifs with unique disulfide-directing capability for regulating the oxidative folding of multicyclic peptides. We demonstrate that incorporating these motifs into random sequences allows the design of disulfide-directed multicyclic peptide (DDMP) libraries with up to four disulfide bonds, which have been applied for the successful discovery of peptide binders with nanomolar affinity to several challenging targets. This study encourages the use of more diverse disulfide-directing motifs for creating multicyclic peptide libraries and opens an avenue for discovering functional peptides in sequence and structural space beyond existing peptide scaffolds, potentially advancing the field of peptide drug discovery.
(© 2024. The Author(s).)

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92356308 National Natural Science Foundation of China (National Science Foundation of China); 22174119 National Natural Science Foundation of China (National Science Foundation of China)

0 (Disulfides)
K848JZ4886 (Cysteine)
0 (Peptide Library)
0 (Peptides)
0 (Peptides, Cyclic)

Date Created: 20240906 Date Completed: 20240906 Latest Revision: 20240910

20250114

PMC11379947

10.1038/s41467-024-51723-w

39242578