Antimyristoylation of the gag proteins in the human immunodeficiency virus-infected cells with N-myristoyl glycinal diethylacetal resulted in inhibition of virus production

Tashiro, Akari; Shoji, Shuichi; Kubota, Yukiho

doi:10.1016/0006-291x(89)92722-8

Cited by 30 publications

(16 citation statements)

References 19 publications

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“…The attachment of myristic acid to proteins is catalysed by the enzyme myristoylCoA:protein N-myristoyltransferase (NMT) (Harper & Gilbert, 1992;McIlhinney, 1990;Schmidt, 1989, Towler et al, 1988, which attaches myristic acid to an aminoterminal glycine with high substrate specificity. Inhibitors of myristoylation and analogues of myristic acid inhibit replication of some retroviruses, including human immunodeficiency virus (HIV) (Bryant et al, 1989, t991 ;Devadas et al, 1992;Saermark et al, 1991;Tashiro et al, 1990) but these studies have not been extended to any other virus family. We have studied the effect of OL-2-hydroxymyristic acid (2-HM) on varicella-zoster virus (human herpesvirus 3, VZV) using a plaque reduction assay together with studies of viral anabolism.…”

Section: Inhibition Of Varicella-zoster Virus Replication By An Inhibmentioning

confidence: 99%

Inhibition of varicella-zoster virus replication by an inhibitor of protein myristoylation

Harper

Gilbert

Blunt

et al. 1993

Journal of General Virology

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Section: Inhibition Of Varicella-zoster Virus Replication By An Inhibmentioning

confidence: 99%

Inhibition of varicella-zoster virus replication by an inhibitor of protein myristoylation

Harper

Gilbert

Blunt

et al. 1993

Journal of General Virology

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“…For example, the nonmyristoylated Gag protein obtained by amino acid substitution at the N-terminal glycine fails to target to the plasma membrane and produces no virus particles (10,25,23). The use of myristoylation inhibitors, such as analogues of myristic acid and myristoyl-glycine, also produces nonmyristoylated Gag and leads to a severe reduction in infectious particle production, suggesting an effective antivirus therapeutic strategy (11,32,35,58,65).…”

mentioning

confidence: 99%

Dominant Negative Inhibition of Human Immunodeficiency Virus Particle Production by the Nonmyristoylated Form of Gag

Kawada

Goto

Haraguchi

et al. 2008

J Virol

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Myristoylation of human immunodeficiency virus (HIV) Gag protein is essential for membrane targeting ofGag and production of viral particles. We show here that coexpression of wild-type and nonmyristoylated forms of HIV Gag resulted in severe inhibition of viral particle production, indicating that the nonmyristoylated counterpart had a dominant negative effect on particle release. When coexpressed, the nonmyristoylated Gag partially incorporated into membrane and lipid raft fractions, likely through coassembly with the wild-type Gag. The membrane and raft associations of the wild-type Gag appeared unaffected, and yet particle production was severely impaired. When viral particles produced from the coexpressing cells were analyzed, the wild-type Gag was more abundant than the nonmyristoylated Gag. Confocal microscopy showed that both forms of Gag were diffusely distributed in the cytoplasm of coexpressing cells but that a portion of the wild-type Gag population was accumulated in EEA1-and CD63-positive endosomes. The intracellular accumulation of Gag was more frequently observed at late time points. The Gag accumulation was also observed on the cell surface protrusion. Electron microscopy of the coexpressing cells revealed budding arrest phenotypes, including the occurrence of interconnected virions on the plasma membrane, and intracellular budding. We also show that the inhibition of particle production and the Gag accumulation to endosomes were suppressed when the nucleocapsid (NC) domain was deleted from the nonmyristoylated Gag, although the NC-deleted Gag was still capable of coassembly. Overall, our data indicate that coassembly with the nonmyristoylated Gag impairs HIV particle release, a phenomenon that may involve NC-mediated Gag-Gag interaction.

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“…Heteroatom-substituted analogues of myristic acid (15), phospholipid containing such a myristic acid analogue (16), and analogues of N-myristoyl glycine (17)(18)(19) have been reported to inhibit HIV replication, and most of these inhibitors are expected to inhibit N-myristoyltransferase activity. However, the biochemical characterization of these compounds in relation to their effect on HIV remains poorly understood, and precise correlation between Gag myristoylation and HIV particle formation remains unclear.…”

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confidence: 99%

Complete Inhibition of Human Immunodeficiency Virus Gag Myristoylation Is Necessary for Inhibition of Particle Budding

Morikawa

Hinata

Tomoda

et al. 1996

Journal of Biological Chemistry

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Myristoylation of human immunodeficiency virus (HIV)Gag protein is essential for virus particle budding. Two reactions are involved; activation of free myristate to myristoyl-CoA and transfer of the myristoyl residue to the Gag N-terminal glycine. We have investigated the effects of triacsin C, an inhibitor of long chain acyl-CoA synthetase, on release of HIV Gag virus-like particle (VLP) produced using the recombinant baculovirus system. First, inhibition of acyl-CoA formation by triacsin C was confirmed using the membrane fractions of insect Sf9 cells as an enzyme source. Second, when HIV Gag protein was expressed in the presence of triacsin C (0 -48 M), Gag myristoylation was inhibited in a dosedependent manner. Budding of Gag VLP, however, did not follow similar inhibition kinetics but appeared unaffected up to 24 M, yet was completely abolished at 48 M when the myristoylation of Gag protein was also completely inhibited. The "all-or-none" inhibition of Gag VLP budding suggests that although inhibition of acyl-CoA synthetase blocks the production of myristoylated Gag protein, only complete inhibition of Gag myristoylation prevents VLP budding. Thus, relatively few myristoylated Gag molecules are sufficient for plasma membrane targeting and VLP budding.

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Antimyristoylation of the gag proteins in the human immunodeficiency virus-infected cells with N-myristoyl glycinal diethylacetal resulted in inhibition of virus production

Cited by 30 publications

References 19 publications

Inhibition of varicella-zoster virus replication by an inhibitor of protein myristoylation

Inhibition of varicella-zoster virus replication by an inhibitor of protein myristoylation

Dominant Negative Inhibition of Human Immunodeficiency Virus Particle Production by the Nonmyristoylated Form of Gag

Complete Inhibition of Human Immunodeficiency Virus Gag Myristoylation Is Necessary for Inhibition of Particle Budding

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