Identification of a macrocyclic compound targeting the lassa virus polymerase

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dc.contributor.authorAida-Ficken, Virginia
dc.contributor.authorKelly, Jamie A.
dc.contributor.authorChatterjee, Payel
dc.contributor.authorJenks, M. Harley
dc.contributor.authorMcMullan, Laura K.
dc.contributor.authorAlbariño, César G.
dc.contributor.authorMontgomery, Joel M.
dc.contributor.authorSeley-Radtke, Katherine L.
dc.contributor.authorSpiropoulou, Christina F.
dc.contributor.authorFlint, Mike
dc.date.accessioned2025-04-01T14:55:15Z
dc.date.available2025-04-01T14:55:15Z
dc.date.issued2024-08-01
dc.description.abstractThere 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.
dc.description.sponsorshipWe thank Constantinos Kyriakis for supervising VAF through her graduate program and providing insightful discussion and Tanya Klimova for expert assistance in editing this manuscript. We thank the Emory Institute for Drug Development for the kind gift of 4?-FlU. VAF holds a fellowship supported by the National Bio and Agro Defense Facility Scientist Training Program (NSTP) administered by Auburn University through an interagency agreement between the United States Department of Agriculture (USDA) and Animal and Plant Health Inspection Services (APHIS) and CDC. This work was in part supported by the USDA-APHIS NSTP (Grant number AP19VSNVSL00C003), the Defense Threat Reduction Agency (DTRA, grant HDTRA1241740), CDC Office of Advanced Molecular Detection, CDC Emerging Infectious Disease Research Core Funds, and by appointments to the CDC (JAK) administered by the Oak Ridge Institute for Science and Education (ORISE). ORISE is managed by Oak Ridge Associated Universities (ORAU) under contract with the U.S. Department of Energy (DOE).
dc.description.urihttps://www.sciencedirect.com/science/article/pii/S0166354224001323
dc.format.extent10 pages
dc.genrejournal articles
dc.identifierdoi:10.13016/m25hbf-v18n
dc.identifier.citationAida-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.
dc.identifier.urihttps://doi.org/10.1016/j.antiviral.2024.105923
dc.identifier.urihttp://hdl.handle.net/11603/37876
dc.language.isoen_US
dc.publisherElsevier
dc.relation.isAvailableAtThe University of Maryland, Baltimore County (UMBC)
dc.relation.ispartofUMBC Chemistry & Biochemistry Department
dc.relation.ispartofUMBC Faculty Collection
dc.rightsThis 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.
dc.rightsPublic Domain
dc.rights.urihttps://creativecommons.org/publicdomain/mark/1.0/
dc.subjectAntiviral
dc.subjectLassa
dc.subjectPolymerase
dc.subjectMacrocycle
dc.titleIdentification of a macrocyclic compound targeting the lassa virus polymerase
dc.typeText
dcterms.creatorhttps://orcid.org/0000-0002-0154-3459

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