1. Cellular N-Myristoyl Transferases Are Required for Mammarenavirus Multiplication.
- Author
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Witwit, Haydar, Betancourt, Carlos Alberto, Cubitt, Beatrice, Khafaji, Roaa, Kowalski, Heinrich, Jackson, Nathaniel, Ye, Chengjin, Martinez-Sobrido, Luis, and de la Torre, Juan C.
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LYMPHOCYTIC choriomeningitis virus , *EXTRACELLULAR matrix proteins , *PEPTIDES , *MYRISTOYLATION , *PROTEOLYSIS - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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