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Inhibition of host N-myristoylation compromising the infectivity of SARS-CoV-2 due to Golgi-bypassing egress

ABSTRACT: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused coronavirus disease 2019 (COVID-19) pandemic, remains a global health crisis despite vaccines, neutralizing antibodies, and antiviral drugs. Emerging mutations can reduce the effectiveness of these treatments, suggesting that targeting host cell factors may be a more robust strategy. Cellular N-myristoyltransferases (NMTs) are essential enzymes for protein myristoylation, affecting stability, interaction, localization, and function of numerous proteins involved in intracellular membrane trafficking. We demonstrate that selective inhibition of host cell NMT1 and -2 by IMP-1088 decrease SARS-CoV-2 infection by 90% in human lung and primary nasal epithelial cells, as well as in human 3D choroid plexus-cortical organoids. NMT1 and -2 inhibition does not affect viral entry, replication, or release, but instead impairs viral assembly and maturation, leading to compromised infectivity of released virions. We further show that inhibition of host NMT1 and -2 triggers an alternative Golgi-bypassing pathway for SARS-CoV-2 progeny virions release, which occurs through a lysosomal intermediate.

ORGANISM(S): Homo sapiens

PROVIDER: GSE268178 | GEO | 2025/09/29

REPOSITORIES: GEO

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