Inhibition of vaccinia virus L1 N-myristoylation by the host N-myristoyltransferase inhibitor IMP-1088 generates non-infectious virions defective in cell entry.
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 in...
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| Format: | Article |
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Public Library of Science (PLoS)
2022-10-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1010662&type=printable |
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| _version_ | 1850060279021305856 |
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| author | Lalita Priyamvada Wouter W Kallemeijn Monica Faronato Kimberly Wilkins Cynthia S Goldsmith Catherine A Cotter Suany Ojeda Roberto Solari Bernard Moss Edward W Tate Panayampalli Subbian Satheshkumar |
| author_facet | Lalita Priyamvada Wouter W Kallemeijn Monica Faronato Kimberly Wilkins Cynthia S Goldsmith Catherine A Cotter Suany Ojeda Roberto Solari Bernard Moss Edward W Tate Panayampalli Subbian Satheshkumar |
| author_sort | Lalita Priyamvada |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-1b85968db8404d64b270c818449b4213 |
| institution | DOAJ |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2022-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-1b85968db8404d64b270c818449b42132025-08-20T02:50:37ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742022-10-011810e101066210.1371/journal.ppat.1010662Inhibition of vaccinia virus L1 N-myristoylation by the host N-myristoyltransferase inhibitor IMP-1088 generates non-infectious virions defective in cell entry.Lalita PriyamvadaWouter W KallemeijnMonica FaronatoKimberly WilkinsCynthia S GoldsmithCatherine A CotterSuany OjedaRoberto SolariBernard MossEdward W TatePanayampalli Subbian SatheshkumarWe 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.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1010662&type=printable |
| spellingShingle | Lalita Priyamvada Wouter W Kallemeijn Monica Faronato Kimberly Wilkins Cynthia S Goldsmith Catherine A Cotter Suany Ojeda Roberto Solari Bernard Moss Edward W Tate Panayampalli Subbian Satheshkumar Inhibition of vaccinia virus L1 N-myristoylation by the host N-myristoyltransferase inhibitor IMP-1088 generates non-infectious virions defective in cell entry. 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. |
| title_full | Inhibition of vaccinia virus L1 N-myristoylation by the host N-myristoyltransferase inhibitor IMP-1088 generates non-infectious virions defective in cell entry. |
| title_fullStr | Inhibition of vaccinia virus L1 N-myristoylation by the host N-myristoyltransferase inhibitor IMP-1088 generates non-infectious virions defective in cell entry. |
| title_full_unstemmed | Inhibition of vaccinia virus L1 N-myristoylation by the host N-myristoyltransferase inhibitor IMP-1088 generates non-infectious virions defective in cell entry. |
| title_short | Inhibition of vaccinia virus L1 N-myristoylation by the host N-myristoyltransferase inhibitor IMP-1088 generates non-infectious virions defective in cell entry. |
| title_sort | inhibition of vaccinia virus l1 n myristoylation by the host n myristoyltransferase inhibitor imp 1088 generates non infectious virions defective in cell entry |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1010662&type=printable |
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