Cellular N-Myristoyl Transferases Are Required for Mammarenavirus Multiplication

Area of Science:

• Virology
• Molecular Biology
• Drug Discovery

Background:

• Mammarenavirus assembly, egress, and cell entry rely on the matrix Z protein and surface glycoproteins (GP1/GP2).
• N-terminal myristoylation of Z protein and stable signal peptide (SSP) by N-myristoyltransferases (NMT1/NMT2) is crucial for viral functions.
• Myristoylation-deficient mutations impair Z-mediated budding and GP2-mediated fusion, essential for viral replication.

Purpose of the Study:

• To investigate the antiviral potential of the pan-NMT inhibitor DDD85646 against pathogenic mammarenaviruses.
• To elucidate the mechanism of DDD85646's antiviral activity, focusing on Z protein and glycoprotein functions.

Main Methods:

• Treatment of cells infected with lymphocytic choriomeningitis virus (LCMV), Junin virus (JUNV), and Lassa virus (LASV) with DDD85646.
• Assessment of viral budding, cell-cell fusion, Z protein levels, and proteasomal degradation.
• Evaluation of DDD85646's on-target specificity and pan-NMT inhibitory activity.

Main Results:

• DDD85646 demonstrated potent antiviral activity against LCMV, JUNV, and LASV.
• The antiviral effect correlated with reduced Z protein budding activity and GP2-mediated fusion.
• DDD85646 induced proteasome-mediated degradation of the Z protein.

Conclusions:

• N-myristoyltransferase (NMT) inhibition represents a viable broad-spectrum antiviral strategy against human pathogenic mammarenaviruses.
• DDD85646 effectively targets critical steps in mammarenavirus replication, including viral assembly and entry.
• Further exploration of NMT inhibitors is warranted for developing new treatments for mammarenaviral infections.