Aida-Ficken, VirginiaKelly, Jamie A.Chatterjee, PayelJenks, M. HarleyMcMullan, Laura K.Albariño, César G.Montgomery, Joel M.Seley-Radtke, Katherine L.Spiropoulou, Christina F.Flint, Mike2025-04-012025-04-012024-08-01Aida-Ficken, Virginia, Jamie A. Kelly, Payel Chatterjee, M. Harley Jenks, Laura K. McMullan, César G.. Albarino, Joel M. Montgomery, Katherine L. Seley-Radtke, Christina F. Spiropoulou, and Mike Flint. "Identification of a Macrocyclic Compound Targeting the Lassa Virus Polymerase." Antiviral Research 228 (August 1, 2024): 105923. https://doi.org/10.1016/j.antiviral.2024.105923.https://doi.org/10.1016/j.antiviral.2024.105923http://hdl.handle.net/11603/37876There are no approved vaccines or therapeutics for Lassa virus (LASV) infections. To identify compounds with anti-LASV activity, we conducted a cell-based screening campaign at biosafety level 4 and tested almost 60,000 compounds for activity against an infectious reporter LASV. Hits from this screen included several structurally related macrocycles. The most potent, Mac128, had a sub-micromolar EC50 against the reporter virus, inhibited wild-type clade IV LASV, and reduced viral titers by 4 orders of magnitude. Mechanistic studies suggested that Mac128 inhibited viral replication at the level of the polymerase.10 pagesen-USThis work was written as part of one of the author's official duties as an Employee of the United States Government and is therefore a work of the United States Government. In accordance with 17 U.S.C. 105, no copyright protection is available for such works under U.S. Law.Public Domainhttps://creativecommons.org/publicdomain/mark/1.0/AntiviralLassaPolymeraseMacrocycleText