Screening and Identification of Lassa Virus Entry Inhibitors from a Fragment-Based Drug Discovery Library.
Viruses
; 14(12)2022 11 27.
Article
en En
| MEDLINE
| ID: mdl-36560653
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Arenaviridae
/
Inhibidores de Fusión de VIH
/
Fiebre de Lassa
Tipo de estudio:
Diagnostic_studies
/
Screening_studies
Límite:
Humans
Idioma:
En
Revista:
Viruses
Año:
2022
Tipo del documento:
Article
País de afiliación:
China