Mammarenavirus Z protein myristoylation and oligomerization are not required for its dose-dependent inhibitory effect on vRNP activity

We have recently documented the use of N-Myristoyltransferase inhibitors (NMTi) as an antiviral strategy against human pathogenic mammarenaviruses, including Lassa and Junin viruses, responsible for the hemorrhagic fever (HF) diseases Lassa fever (LF) and Argentine HF (AHF), respectively. Mammarenavirus Z matrix protein has been shown to exert a dose-dependent inhibitory effect in the activity of the virus ribonucleoprotein (vRNP) complex responsible for directing replication and transcription of the viral genome. Prevention of Z myristoylation by NMTi targeted Z protein for degradation, which resulted in inhibition of virus multiplication. Here, we review the recent findings of the use NMTi as antiviral, and reconcile the mechanistic process behind this inhibitory effect, more importantly, we used NMTi and G2A-mutated Z protein as a control of myristoylation function of wild type Z protein to elucidate that the vRNP suppression is monomeric-dependent activity of Z protein abundancy and it is independent of its myristoylation function.