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

ABSTRACT: 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 aff

SUBMITTER: Duan Z 

PROVIDER: S-EPMC11379947 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature