Discovery of a cell-active chikungunya virus nsP2 protease inhibitor using a covalent fragment-based screening approach.
Eric M MertenJohn D SearsTina M LeisnerPaul B HardyAnirban GhoshalMohammad Anwar HossainKesatebrhan Haile AsressuPeter J BrownMichael A StashkoLaura HerringAngie L MordantThomas S WebbChristine A MillsNatalie K BarkerZachary J StreblowSumera PerveenCheryl ArrowsmithJamie J ArnoldCraig E CameronDaniel N StreblowNathaniel J MoormanMark HeiseTimothy M WillsonKonstantin PopovKenneth H PearcePublished in: bioRxiv : the preprint server for biology (2024)
Chikungunya virus is one of the most prominent and widespread alphaviruses and has caused explosive outbreaks of arthritic disease. Currently, there are no FDA-approved drugs to treat disease caused by chikungunya virus or any other alphavirus-caused infection. Here, we report the discovery of a covalent small molecule inhibitor of chikungunya virus nsP2 protease activity and viral replication of four diverse alphaviruses. This finding highlights the utility of covalent fragment screening for inhibitor discovery and represents a starting point towards the development of alphavirus therapeutics targeting nsP2 protease.