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bioRxiv · 10.1101/2024.08.01.606235

Cellular N-myristoyl transferases Are Required for Mammarenavirus Multiplication

Witwit, H.·Betancourt, C.·Cubitt, B.·Khafaji, R.·Kowalski, H.·Jackson, N.·Ye, C.·Martinez-Sobrido, L.·de la Torre, J. C.
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Abstract

The mammarenavirus matrix Z protein plays critical roles in virus assembly and cell egress, whereas 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 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 Z mediated virus budding and GP2 mediated fusion activity required to complete the virus cell entry process. In the present work, we present evidence that the validated on-target specific pan NMT inhibitor DDD85464 exerts a potent antiviral activity against the prototypic mammarenavirus lymphocytic choriomeningitis virus (LCMV) that correlated with reduced Z budding activity and GP2 mediated fusion activity, as well as proteasome mediated degradation of the Z protein. The potent anti-mammarenaviral activity of DDD85646 was also observed with the hemorrhagic fever causing mammarenaviruses Junin (JUNV) and Lassa (LASV) viruses. Our results support exploration of NMT inhibition as a broad-spectrum antiviral against human pathogenic mammarenaviruses.

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Witwit, H., Betancourt, C., Cubitt, B., Khafaji, R., Kowalski, H., Jackson, N., Ye, C., Martinez-Sobrido, L., de la Torre, J. C.. 2024-08-01. Cellular N-myristoyl transferases Are Required for Mammarenavirus Multiplication. https://doi.org/10.1101/2024.08.01.606235

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