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MyristolyCoA:protein N-myristoyltransferase as a therapeutic target for inhibiting replication of human immunodeficiency virus-1

  • Perspectives
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Perspectives in Drug Discovery and Design

Summary

Human myristoylCoA:protein N-myristoyltransferase (hNmt) is a 416-residue, monomeric enzyme that catalyzes the covalent attachment of myristate (C14:0), via an amide bond, to the amino-terminal glycine residue of several proteins encoded by the HIV-1 genome. These proteins include Pr160gag-pol, Pr55gag, the capsid protein p17 derived from proteolytic processing of gag, and negative factor (nef). N-myristoylation of Pr160gag-pol and Pr55gag is required for viral replication. Recent genetic and biochemical studies have provided insights about the hNmt's structure-function relationships, acylCoA and peptide substrate specificities, as well as its kinetic mechanism. Based on the results of host-guest studies, myristic acid analogs have been designed that are substrates for cellular myristoylCoA synthetases and Nmt both in vitro and in vivo. These analogs are selectively incorporated into subsets of cellular and viral N-myristoylproteins. Incorporation can produce analog- and protein-specific alterations in function. In the case of HIV-1, certain oxatetradecanoic acids cause redistribution of Pr55gag from membrane to cytosolic fractions, a reduction in its proteolytic processing, and an inhibition of viral replication in acutely and chronically infected T-lymphocytes at doses that do not cause cellular toxicity. Members of this class of compounds also are fungicidal — producing a rapid and marked reduction in the viability ofC. neoformans. This raises the possibility that Nmt may be an attractive therapeutic target for inhibiting HIV-1 replication in AIDS patients and for treating certain of their opportunistic infections.

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  1. G.D. Searle Company, 63198, St. Louis, MO, USA

    Martin L. Bryant, Charles A. McWherter & Nandini S. Kishore

  2. Department of Chemistry, University of Miami, 33124, Coral Gables, FL, USA

    George W. Gokel

  3. Department of Molecular Biology and Pharmacology, Washington University School of Medicine, 63110, St. Louis, MO, USA

    Jeffrey I. Gordon

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  1. Martin L. Bryant
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Bryant, M.L., McWherter, C.A., Kishore, N.S. et al. MyristolyCoA:protein N-myristoyltransferase as a therapeutic target for inhibiting replication of human immunodeficiency virus-1. Perspectives in Drug Discovery and Design 1, 193–209 (1993). https://doi.org/10.1007/BF02171662

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