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

Harper, David R.; Gilbert, Ruth; Blunt, C.; McIlhinney, R. A. Jeffrey

doi:10.1099/0022-1317-74-6-1181

Cited by 33 publications

(15 citation statements)

References 19 publications

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“…Its low IG so of 22 f-LM in these assays compares favourably with that of acyclovir (Harper et al, 1993). These results correspond also with those found by Paige et al (1990) when they compared the 2-bromo, 2-f1uoro and 2-hydroxy substituted derivatives of 2-hydroxytetradecanoic acid and found that 2-hydroxytetradecanoic acid had the greatest inhibitory effect on protein myristoylation in cell culture.…”

Section: Effect Of Myristoylation Inhibitors On Vzv 183supporting

confidence: 76%

“…Using plaque reduction assays, the authors studied the effects of proposed myristoylation inhibitors (provided from the Medical Research Council AIDS-directed programme) on the replication of varicella-zoster virus (human herpesvirus 3, VZV) (Harper et al, 1993). VZV had been shown previously to produce myristoylproteins including the immunogenic major viral glycoprotein V2VgE (gp1)and the smaller Lp7 (Lipoprotein 7, molecular weight 7000; Harper and Kangro, 1990), suggesting that it might be subject to inhibition by such compounds.…”

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confidence: 99%

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Effect of Inhibitors of Protein Myristoylation on Varicella-Zoster Virus Replication

Gilbert

Blunt

Harper

et al. 1994

Antivir Chem Chemother

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SummaryInhibitors of N-myristoyltransferase (NMT) have been shown to inhibit retrovirus replication, notably that of the human immunodeficiency virus (HIV), where the absence of protein myristoylation inhibits viral replication. The authors have assayed 14 compounds derived from myristic acid for activity against varicella-zoster virus (human herpesvirus 3; VZV) by plaque reduction assay. Seven showed cytotoxicity and of the others, two failed to inhibit VZV replication. One of these was N-myristoylglycinaldiethylacetal (GoA), which has been reported to be active against HIV. 12-(methoxy) dodecanoic acid (13-oxamyristic acid), which has also been reported to inhibit HIV replication, was found to inhibit VZV replication but was cytotoxic at high concentrations. The greatest inhibitory effect without apparent toxicity was induced by 2-hydroxytetradecanoic acid and its enantiomers. The results of these assays provide further evidence that inhibitors of NMT have potential as antiViral agents against the many viruses with myristoylated proteins.Myristic acid constitutes approximately 1% of cellular fatty acids in mammalian cells (Heuckeroth et aI., 1990) and is attached to the N-terminal glycine residue of proteins by the enzyme myristoyl-CoA:Protein N-myristoyltransferase (NM1). Sequence analyses of this enzyme have shown it to be highly conserved between species suggesting an important role in cell functions in both prokaryotes and eukaryotes.Acylated proteins have been shown to playa range of important roles in both cellular and viral metabolism and it

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Section: Effect Of Myristoylation Inhibitors On Vzv 183supporting

confidence: 76%

mentioning

confidence: 99%

Effect of Inhibitors of Protein Myristoylation on Varicella-Zoster Virus Replication

Gilbert

Blunt

Harper

et al. 1994

Antivir Chem Chemother

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“…2-OHM is an analog of myristic acid that becomes metaboli- (28). Treatment of cells with 2-OHM results in reduced protein myristoylation while protein synthesis remains unaffected (15). Moreover, 2-OHM specifically inhibits myristoylation, whereas other protein acylation events, such as posttranslational palmitoylation, are not altered (28).…”

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confidence: 99%

“…Inhibitors of myristoylation, like 2-OHM, have been reported to affect the multiplication of viruses known to produce myristoylated proteins, such as human immunodeficiency virus (5), Varicella-Zoster virus (15), and hepatitis B virus (29). In addition, two New World arenaviruses, Junin and Tacaribe, were inhibited by treatment with inhibitors of myristoylation (9), although the viral proteins targeted by the inhibitors were not identified.…”

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Myristoylation of the RING Finger Z Protein Is Essential for Arenavirus Budding

Perez

Greenwald

Torre

2004

J Virol

125

123

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The arenavirus small RING finger Z protein is the main driving force of arenavirus budding. The primary structure of Z is devoid of hydrophobic transmembrane domains, but both lymphocytic choriomeningitis virus (LCMV) and Lassa fever virus Z proteins accumulate near the inner surface of the plasma membrane and are strongly membrane associated. All known arenavirus Z proteins contain a glycine (G) at position 2, which is a potential acceptor site for a myristoyl moiety. Metabolic labeling showed incorporation of [ 3 H]myristic acid by wild-type Z protein but not by the G2A mutant. The mutation G2A eliminated Z-mediated budding. Likewise, treatment with the myristoylation inhibitor 2-hydroxymyristic acid inhibited Z-mediated budding, eliminated formation of virus-like particles, and caused a dramatic reduction in virus production in LCMVinfected cells. Budding activity was restored in G2A mutant Z proteins by the addition of the myristoylation domain of the tyrosine protein kinase Src to their N termini. These findings indicate N-terminal myristoylation of Z plays a key role in arenavirus budding.

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“…Nmt is a potential target for antiviral (2)(3)(4), antifungal (5-7), and antineoplastic therapy (8 -10).…”

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Biochemical Studies of Saccharomyces cerevisiae Myristoyl-coenzyme A:Protein N-Myristoyltransferase Mutants

Zhang

Jackson-Machelski

Gordon

1996

Journal of Biological Chemistry

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Saccharomyces cerevisiae myristoyl-CoA:protein Nmyristoyltransferase (Nmt1p) is an essential 455-residue, monomeric enzyme that catalyzes the transfer of myristate from myristoyl-CoA to the NH 2 -terminal Gly residue of cellular proteins. Nmt1p has an ordered Bi Bi reaction mechanism with binding of myristoyl-CoA occurring before binding of peptide substrates. To define residues important for function, the polymerase chain reaction was used to generate random mutations in the NMT1 gene. A colony color sectoring assay was used to screen a library of 52,000 transformants for nmt1 alleles encoding enzymes with reduced activity. nmt1 alleles were identified that produced temperature-sensitive (ts) growth arrest due to substitutions affecting eight residues conserved in orthologous Nmts: 217 3 Arg produces 3-and 6-fold increases in K i for SC-58272 at 24 and 37°C but no change in K i for S-(2-oxo)pentadecylCoA, indicating that the substitution selectively affects Nmt1p's peptide binding site. Asn 426 3 Ile selectively perturbs the myristoyl-CoA binding site, resulting in the most pronounced reduction in affinity for S-(2-oxo)pentadecyl-CoA (12-and 20-fold). Ala 202 3 Thr, which confers the most severe ts phenotype, provides an example of a substitution that affects both sites, producing 3-and 6-fold increases in the K i for S-(2-oxo)pentadecyl-CoA and 6-and 9-fold increases in the K i for SC-58272 at 24 and 37°C. An N-myristoylation-dependent change in the electrophoretic mobility of Arf1p was used to assay the effects of the mutants on cellular levels of protein Nmyristoylation under a variety of growth conditions. The ts growth arrest produced by nmt1 alleles correlates with a reduction in myristoyl-Arf1p to 50% of total cellular Arf1p.

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

Cited by 33 publications

References 19 publications

Effect of Inhibitors of Protein Myristoylation on Varicella-Zoster Virus Replication

Effect of Inhibitors of Protein Myristoylation on Varicella-Zoster Virus Replication

Myristoylation of the RING Finger Z Protein Is Essential for Arenavirus Budding

Biochemical Studies of Saccharomyces cerevisiae Myristoyl-coenzyme A:Protein N-Myristoyltransferase Mutants

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