RFdiffusion-peptides targeting Listeria prfA dimer-interfaces

Peptide-binders have been generated by Rosetta-Fold diffusion (RFdiffusion) against the dimer-interfaces of the positive regulatory factor A (prfA) regulon of Listeria monocitogenes (Lm). Lm are amongst those raising worldwide concerns because of their multiple-resistant food-borne infective intracellular Gram-positive bacterial strains . PrfA is a Lm dimer protein that binds to many DNA palindromic transcriptional operators to trigger coordinated gene expression responses to environment, food and/or virulent infections. Here, we describe the generation by RFdiffusion of linear and cyclic peptide-binders predicting their target to the interface α-helices of prfA. Their predicted low-picoMolar docking affinities suggest they may compete with the prfA dimer formation required for experimental DNA-binding. Their experimental validation as inhibitors of Lm virulence, requires additional peptide chemical or recombinant synthesis.