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

• 成果类型: Article
• 署名作者: Juraszek, Jarek; Kadam, Rameshwar U.; Branduardi, Davide; van Ameijde, Jeroen; Garg, Divita; Dailly, Nicolas; Jongeneelen, Mandy; Vermond, Jan; Brakenhoff, Just P. J.; Brandenburg, Boerries; van Dongen, Maria J. P.; Vogels, Ronald; Friesen, Robert H. E.; Wilson, Ian A.
• 署名单位: Scripps Research Institute; Scripps Research Institute; Scripps Research Institute; Astex Pharmaceuticals
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9418
• DOI: 10.1073/pnas.2426554122
• 发表日期: 2025-07-01
• 关键词: amino-acid scan; mirror-image; inhibitors; optimization; specificity; antagonist; proteins; affinity

摘要

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 virus hemagglutinin, resulting in identification of multiple D-peptide lead series. The X-ray structure of one of the leads at 2.38 & Aring; resolution verifies the validity of the approach. This method should be generally applicable to targets with detailed structural information, independent of molecular size, and accelerate development of stable, peptide-based therapeutics.