New small molecule inhibitors of arenaviruses

DESCRIPTION provided by applicant Lassa fever virus LASV and Machupo virus MACV are hemorrhagic fever arenaviruses which are classified as Category A Agents Currently there are no licensed LASV or MACV vaccines and LASV MACV therapy is limited to use of the nucleoside analog ribavirin which is only partially effective and associated with significant side effects The impact of arenaviruses on public health and biodefense readiness coupled with limited treatment options to combat arenavirus infections underscore the importance of developing novel and effective strategies to combat arenaviruses especially LASV and MACV New small molecule inhibitors would be of paramount importance for use during arenaviral outbreaks or bioterrorist attacks This application defines a plan to develop potent small molecule inhibitors which block entry of LASV and MACV Entry of LASV and MACV into the hosts is mediated by a single viral glycoprotein GP which is considered one of the major therapeutic targets GP consists of three subunits GP GP and a stable signal peptide SSP GP is responsible for receptor binding and host tropism while GP mediates viral cell membrane fusion and viral entry We have used an HTS protocol targeting GP mediated viral entry to screen a small molecule library and we have identified compounds that inhibit entry of LASV and MACV IC values M These hit compounds exhibit selectivity for arenavirus entry The overall objective of this Phase I application is to develop these inhibitors as potentia antiviral therapeutics This application will focus on the following three specific aims Synthesize structurally diverse analogs of the anti arenavirus MBX hit series based on structure activity relationships SARs to improve potency and selectivity Select LASV MACV inhibitors with in vitro ADME properties suitable for i v and oral dosing Validate the lead inhibitor candidates in the infectious assays and investigate the mechanism of action MOA of the LASV MACV inhibitors PUBLIC HEALTH RELEVANCE This project is to discover and develop small molecule entry inhibitors for arenaviruses The proposed research will help to develop potential antiviral therapeutics