RT Journal Article
SR Electronic
T1 Inhibition of vaccinia virus L1 <em>N</em>-myristoylation by the host <em>N</em>-myristoyltransferase inhibitor IMP-1088 generates non-infectious virions defective in cell entry
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.06.13.495866
DO 10.1101/2022.06.13.495866
A1 Lalita Priyamvada
A1 Wouter W. Kallemeijn
A1 Monica Faronato
A1 Kimberly Wilkins
A1 Cynthia S. Goldsmith
A1 Catherine A. Cotter
A1 Suany Ojeda
A1 Roberto Solari
A1 Bernard Moss
A1 Edward W. Tate
A1 Panayampalli Subbian Satheshkumar
YR 2022
UL http://biorxiv.org/content/early/2022/06/13/2022.06.13.495866.abstract
AB We have recently shown that the replication of rhinovirus, poliovirus and foot-and-mouth disease virus requires the co-translational N-myristoylation of viral proteins by human host cell N-myristoyltransferases (NMTs), and is inhibited by treatment with IMP-1088, an ultrapotent small molecule NMT inhibitor. Here, we reveal the role of N-myristoylation during vaccinia virus (VACV) infection in human host cells and demonstrate the anti-poxviral effects of IMP-1088. N-myristoylated proteins from VACV and the host were metabolically labelled with myristic acid alkyne during infection using quantitative chemical proteomics. We identified VACV proteins A16, G9 and L1 to be N-myristoylated. Treatment with NMT inhibitor IMP-1088 potently abrogated VACV infection, while VACV gene expression, DNA replication, morphogenesis and EV formation remained unaffected. Importantly, we observed that loss of N-myristoylation resulted in greatly reduced infectivity of assembled mature virus particles, characterized by significantly reduced host cell entry and a decline in membrane fusion activity of progeny virus. While the N-myristoylation of VACV entry proteins L1, A16 and G9 was inhibited by IMP-1088, mutational and genetic studies demonstrated that the N-myristoylation of L1 was the most critical for VACV entry. Given the significant genetic identity between VACV, monkeypox virus and variola virus L1 homologs, our data provides a basis for further investigating the role of N-myristoylation in poxviral infections as well as the potential of selective NMT inhibitors like IMP-1088 as broad-spectrum poxvirus inhibitors.Competing Interest StatementRS is CEO of Myricx Pharma Ltd. EWT is a founder and Director of Myricx Pharma Ltd.