Viruses traverse the human proteome through peptide interfaces that can be biomimetically leveraged for drug discovery

• 成果类型: Article
• 署名作者: Schickin, Laurene Meyniel; Amaudrut, Jerome; Mallinjoud, Pierre; Guillier, Fabrice; Mangeot, Philippe E.; Lines, Laetitia; Aublin-Gex, Anne; Scholtes, Caroline; Punginelli, Claire; Joly, Stephane; Vasseur, Florence; Manet, Evelyne; Gruffat, Henri; Henry, Thomas; Halitim, Fares; Paparin, Jean-Laurent; Machin, Peter; Darteil, Raphael; Sampson, Diane; Mikaelian, Ivan; Lane, Lydie; Navratil, Vincent; Golinelli-Coher, Marie-Pierre; Terzi, Fabiola; Andre, Patrice; Lotteau, Vincent; Vonderscher, Jacky; Meldrum, Eric C.; de Chassey, Benoit
• 署名单位: Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Ecole Normale Superieure de Lyon (ENS de LYON); Universite Claude Bernard Lyon 1; Institut National de la Sante et de la Recherche Medicale (Inserm); Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); UNICANCER; Centre Leon Berard; Universite Claude Bernard Lyon 1; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Institut National de la Sante et de la Recherche Medicale (Inserm); Swiss Institute of Bioinformatics; Universite Claude Bernard Lyon 1; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Saclay; Centre National de la Recherche Scientifique (CNRS)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14468
• DOI: 10.1073/pnas.2308776121
• 发表日期: 2024-01-30
• 关键词: activation; database; replication; disease; complex; models; intact

摘要

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.