Cellular N-Myristoyl Transferases Are Required for Mammarenavirus Multiplication

Viruses. 2024 Aug 26;16(9):1362. doi: 10.3390/v16091362.

Abstract

The mammarenavirus matrix Z protein plays critical roles in virus assembly and cell egress. Meanwhile, heterotrimer complexes of a stable signal peptide (SSP) together with glycoprotein subunits GP1 and GP2, generated via co-and post-translational processing of the surface glycoprotein precursor GPC, form the spikes that decorate the virion surface and mediate virus cell entry via receptor-mediated endocytosis. The Z protein and the SSP undergo N-terminal myristoylation by host cell N-myristoyltransferases (NMT1 and NMT2), and G2A mutations that prevent myristoylation of Z or SSP have been shown to affect the Z-mediated virus budding and GP2-mediated fusion activity that is required to complete the virus cell entry process. In the present work, we present evidence that the validated on-target specific pan-NMT inhibitor DDD85646 exerts a potent antiviral activity against the prototypic mammarenavirus lymphocytic choriomeningitis virus (LCMV) that correlates with reduced Z budding activity and GP2-mediated fusion activity as well as with proteasome-mediated degradation of the Z protein. The potent anti-mammarenaviral activity of DDD85646 was also observed with the hemorrhagic-fever-causing Junin (JUNV) and Lassa (LASV) mammarenaviruses. Our results support the exploration of NMT inhibition as a broad-spectrum antiviral against human pathogenic mammarenaviruses.

Keywords: LASV; LCMV; N-myristoyltransferases; antiviral; mammarenavirus; myristoylation; proteasome.

MeSH terms

  • Acyltransferases* / genetics
  • Acyltransferases* / metabolism
  • Animals
  • Antiviral Agents / pharmacology
  • Arenaviridae / genetics
  • Arenaviridae / metabolism
  • Arenaviridae / physiology
  • Cell Line
  • Chlorocebus aethiops
  • HEK293 Cells
  • Humans
  • Lymphocytic choriomeningitis virus* / genetics
  • Lymphocytic choriomeningitis virus* / physiology
  • Vero Cells
  • Virus Assembly
  • Virus Internalization
  • Virus Replication*

Substances

  • glycylpeptide N-tetradecanoyltransferase
  • Acyltransferases
  • Antiviral Agents