Screening and Identification of Lassa Virus Entry Inhibitors from a Fragment-Based Drug Discovery Library.

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  • Additional Information
    • Source:
      Publisher: MDPI Country of Publication: Switzerland NLM ID: 101509722 Publication Model: Electronic Cited Medium: Internet ISSN: 1999-4915 (Electronic) Linking ISSN: 19994915 NLM ISO Abbreviation: Viruses Subsets: MEDLINE
    • Publication Information:
      Original Publication: Basel, Switzerland : MDPI
    • Subject Terms:
      Lassa Fever* ; Arenaviridae* ; HIV Fusion Inhibitors*/therapeutic use; Humans ; Lassa virus ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Drug Discovery
    • Abstract:
      Lassa virus (LASV) is a highly pathogenic virus that is categorized as a biosafety level-4 pathogen. Currently, there are no approved drugs or vaccines specific to LASV. In this study, high-throughput screening of a fragment-based drug discovery library was performed against LASV entry using a pseudotype virus bearing the LASV envelope glycoprotein complex (GPC). Two compounds, F1920 and F1965, were identified as LASV entry inhibitors that block GPC-mediated membrane fusion. Analysis of adaptive mutants demonstrated that the transient mutants L442F and I445S, as well as the constant mutant F446L, were located on the same side on the transmembrane domain of the subunit GP2 of GPC, and all the mutants conferred resistance to both F1920 and F1965. Furthermore, F1920 antiviral activity extended to other highly pathogenic mammarenaviruses, whereas F1965 was LASV-specific. Our study showed that both F1920 and F1965 provide a potential backbone for the development of lead drugs for preventing LASV infection.
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    • Contributed Indexing:
      Keywords: Lassa virus (LASV); fragment-based drug discovery (FBDD) library; glycoprotein complex (GPC); membrane fusion; transmembrane domain (TM)
    • Accession Number:
      0 (Antiviral Agents)
      0 (HIV Fusion Inhibitors)
    • Publication Date:
      Date Created: 20221223 Date Completed: 20221226 Latest Revision: 20230131
    • Publication Date:
      20230201
    • Accession Number:
      PMC9782912
    • Accession Number:
      10.3390/v14122649
    • Accession Number:
      36560653