BibTex format
@article{Priyamvada:2022:10.1371/journal.ppat.1010662,
author = {Priyamvada, L and Kallemeijn, WW and Faronato, M and Wilkins, K and Goldsmith, CS and Cotter, CA and Ojeda, S and Solari, R and Moss, B and Tate, EW and Satheshkumar, PS},
doi = {10.1371/journal.ppat.1010662},
journal = {PLoS Pathogens},
title = {Inhibition of vaccinia virus L1 N-myristoylation by the host N-myristoyltransferase inhibitor IMP-1088 generates non-infectious virions defective in cell entry},
url = {http://dx.doi.org/10.1371/journal.ppat.1010662},
volume = {18},
year = {2022}
}
RIS format (EndNote, RefMan)
TY - JOUR
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 examine the importance of N-myristoylation during vaccinia virus (VACV) infection in primate 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.
AU - Priyamvada,L
AU - Kallemeijn,WW
AU - Faronato,M
AU - Wilkins,K
AU - Goldsmith,CS
AU - Cotter,CA
AU - Ojeda,S
AU - Solari,R
AU - Moss,B
AU - Tate,EW
AU - Satheshkumar,PS
DO - 10.1371/journal.ppat.1010662
PY - 2022///
SN - 1553-7366
TI - Inhibition of vaccinia virus L1 N-myristoylation by the host N-myristoyltransferase inhibitor IMP-1088 generates non-infectious virions defective in cell entry
T2 - PLoS Pathogens
UR - http://dx.doi.org/10.1371/journal.ppat.1010662
UR - https://www.ncbi.nlm.nih.gov/pubmed/36215331
UR - http://hdl.handle.net/10044/1/100091
VL - 18
ER -
