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We present a drug design strategy based on structural knowledge of protein-protein interfaces selected through virus-host coevolution and translated into highly potential small molecules. This approach is grounded on Vinland, the most comprehensive atlas of virus-human protein-protein interactions with annotation of interacting domains. From this inspiration, we identified small viral protein domains responsible for interaction with human proteins. These peptides form a library of new chemical entities used to screen for replication modulators of several pathogens. As a proof of concept, a peptide from a KSHV protein, identified as an inhibitor of influenza virus replication, was translated into a small molecule series with low nanomolar antiviral activity. By targeting the NEET proteins, these molecules turn out to be of therapeutic interest in a nonalcoholic steatohepatitis mouse model with kidney lesions. This study provides a biomimetic framework to design original chemistries targeting cellular proteins, with indications going far beyond infectious diseases., Competing Interests: Competing interests statement:L.M.-S., P. Mallinjoud, R.D., J.V., and B.d.C. are working for ENYO Pharma. L. Lines, J.-L.P., S.J., D.S., and E.C.M. were working for ENYO Pharma. F.H., P. Machin, and I.M. were consultants for ENYO Pharma. J.V. is the CEO of ENYO Pharma. P.A. and V.L. are scientific advisors for ENYO Pharma. F.G. is working for Inventiva. J.A. was working for Inventiva.