tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2025 Jul;122(26):e2426554122.
doi: 10.1073/pnas.2426554122. Epub 2025 Jun 27. De novo design of D-peptide ligands: Application to influenza virus hemagglutinin
Jarek Juraszek[SUP] #[/SUP][SUP] 1 [/SUP], Rameshwar U Kadam[SUP] #[/SUP][SUP] 2 [/SUP], Davide Branduardi[SUP] #[/SUP][SUP] 1 [/SUP], Jeroen van Ameijde[SUP] #[/SUP][SUP] 1 [/SUP], Divita Garg[SUP] 3 [/SUP], Nicolas Dailly[SUP] 1 [/SUP], Mandy Jongeneelen[SUP] 1 [/SUP], Jan Vermond[SUP] 1 [/SUP], Just P J Brakenhoff[SUP] 1 [/SUP], Boerries Brandenburg[SUP] 1 [/SUP], Maria J P van Dongen[SUP] 1 [/SUP], Ronald Vogels[SUP] 1 [/SUP], Robert H E Friesen[SUP] 1 [/SUP], Ian A Wilson[SUP] 2 4 [/SUP]
Affiliations
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 Å 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.
Keywords: D-peptide; X-ray crystallography; computational design; hemagglutinin; influenza
. 2025 Jul;122(26):e2426554122.
doi: 10.1073/pnas.2426554122. Epub 2025 Jun 27. De novo design of D-peptide ligands: Application to influenza virus hemagglutinin
Jarek Juraszek[SUP] #[/SUP][SUP] 1 [/SUP], Rameshwar U Kadam[SUP] #[/SUP][SUP] 2 [/SUP], Davide Branduardi[SUP] #[/SUP][SUP] 1 [/SUP], Jeroen van Ameijde[SUP] #[/SUP][SUP] 1 [/SUP], Divita Garg[SUP] 3 [/SUP], Nicolas Dailly[SUP] 1 [/SUP], Mandy Jongeneelen[SUP] 1 [/SUP], Jan Vermond[SUP] 1 [/SUP], Just P J Brakenhoff[SUP] 1 [/SUP], Boerries Brandenburg[SUP] 1 [/SUP], Maria J P van Dongen[SUP] 1 [/SUP], Ronald Vogels[SUP] 1 [/SUP], Robert H E Friesen[SUP] 1 [/SUP], Ian A Wilson[SUP] 2 4 [/SUP]
Affiliations
- PMID: 40577121
- DOI: 10.1073/pnas.2426554122
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 Å 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.
Keywords: D-peptide; X-ray crystallography; computational design; hemagglutinin; influenza