De novo design of D-peptide ligands: Application to influenza virus hemagglutinin.

ABSTRACT: D-peptides hold great promise as therapeutics by alleviating the challenges of metabolic stability and immunogenicity in L-peptides. However, current D-peptide discovery methods are severely limited by specific size, structure, and the chemical synthesizability of their protein targets. Here, we describe a computational method for de novo design of D-peptides that bind to an epitope of interest on the target protein using Rosetta's hotspot-centric approach. The approach comprises identifying hotspot sidechains in a functional protein-protein interaction and grafting these side chains onto much smaller structured peptide scaffolds of opposite chirality. The approach enables more facile design of D-peptides and its applicability is demonstrated by design of D-peptidic binders of influenza A

SUBMITTER: Juraszek J 

PROVIDER: S-EPMC12232713 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature