Blocking poxvirus infectiousness with NMT inhibitors

Congratulations to Dr Wouter Kallemeijn, Dr Monica Faronato, and collaborating labs on their publication in PLOS Pathogens

Viruses including rhinovirus, poliovirus and foot-and-mouth disease virus depend on several of their proteins being co-translationally N-myristoylated by the human host cell’s N-myristoyltransferases (NMTs). Pharmacological inhibition of N-myristoylation, e.g. by IMP1088 – an extremely potent small molecule developed within the group, halts the replication of these viruses.

In close collaboration with the USA Centers for Disease Control and Prevention (CDC), Dr Wouter Kallemeijn and Dr Monica Faronato discovered that the Vaccinia poxvirus – closely related to Variola, the causative agent of smallpox, as well as the monkeypox virus – depends on N-myristoylation in a similar manner. Now published in PLOS Pathogens, we identified Vaccinia virus depends on the human host cell’s N-myristoylation machinery for the entry/fusion complex to be functional. NMT inhibition renders the Vaccinia virus particles unable to efficiently enter and infect cells.

With the discontinuation of smallpox vaccination programs, waning immunity, political instability, and emerging outbreaks of poxviruses as monkeypox, most of the global population is at risk to these viruses. This requires direct intervention by vaccination or antivirals in the event of exposure. Selective NMT inhibitors such as IMP1088 could lead to broad-spectrum poxvirus inhibitors, by exploiting these viruses’ dependency on human host-cell NMT.

A huge thanks to Lalita Priyamvada, Subbian Satheshkumar (CDC), Roberto Solari (Myricx), and everyone in their teams for the valuable input. Particular thanks to everyone involved in funding this research project.