Incorporation of 12-methoxydodecanoate into the human immunodeficiency virus 1 gag polyprotein precursor inhibits its proteolytic processing and virus production in a chronically infected human lymphoid cell line

Journal Article · Fri Mar 15 00:00:00 EST 1991 · Proceedings of the National Academy of Sciences of the United States of America; (United States)

DOI:https://doi.org/10.1073/pnas.88.6.2055· OSTI ID:5079154

Bryant, M L; Ratner, L; Duronio, R J; Gordon, J I ^[1]; Kishore, N S ^[2]; Devadas, B; Adams, S P ^[3]

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1. Washington Univ. School of Medicine, St. Louis, MO (United States)
2. G.D. Searle, St. Louis, MO (United States)
3. Monsanto Co., St. Louis, MO (United States)

Covalent linkage of myristate (tetradecanoate; 14:0) to the NH{sub 2}-terminal glycine residue of the human immunodeficiency virus 1 (HIV-1) 55-kDa gag polyprotein precursor (Pr55{sup gag}) is necessary for its proteolytic processing and viral assembly. The authors have shown recently that several analogs of myristate in which a methylene group is replaced by a single oxygen or sulfur atom are substrates for Saccharomyces cerevisiae and mammalian myristoyl-CoA:protein N-myristoyltransferase despite their reduced hydrophobicity. To examine the mechanism of their antiviral effects, they performed labeling studies with two analogs, 12-methoxydodecanoate (13-oxamyristate; 13-OxaMyr) and 5-octyloxypentanoate (6-oxamyristate; 6-OxaMyr), the former being much more effective than the latter in blocking virus production. ({sup 3}H)Myristate and ({sup 3}H)13-OxaMyr were incorporated into Pr55{sup gag} with comparable efficiency when it was coexpressed with S. cerevisiae NMT in Escherichia coli. Unlike AZT, the analog is able to inhibit virus production (up to 70%) in chronically infected H9 cells. Moreover, the inhibitory effect lasts 6-8 days. These results suggest that (i) its mechanism of action is distinct from that of AZT and involves a late step in virus assembly; (ii) the analog may allow reduction in the dose of AZT required to affect viral replication; and (iii) combinations of analog and HIV-1 protease inhibitors may have synergistic effects on the processing of Pr55{sup gag}.

• OSTI ID: 5079154
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (United States), Vol. 88:6; ISSN 0027-8424
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
AIDS VIRUS
INACTIVATION
ANTI-INFECTIVE AGENTS
BIOLOGICAL EFFECTS
TETRADECANOIC ACID
UPTAKE
AIDS
BIOCHEMISTRY
DECANOIC ACID
ESCHERICHIA COLI
GLYCINE
LYMPHOCYTES
SACCHAROMYCES
THYMIDINE
TRITIUM COMPOUNDS
AMINO ACIDS
ANIMAL CELLS
AZINES
BACTERIA
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BODY FLUIDS
CARBOXYLIC ACIDS
CHEMISTRY
CONNECTIVE TISSUE CELLS
DISEASES
DRUGS
EUMYCOTA
FUNGI
HETEROCYCLIC COMPOUNDS
HYDROGEN COMPOUNDS
IMMUNE SYSTEM DISEASES
INFECTIOUS DISEASES
LEUKOCYTES
MATERIALS
MICROORGANISMS
MONOCARBOXYLIC ACIDS
NUCLEOSIDES
NUCLEOTIDES
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PARASITES
PLANTS
PYRIMIDINES
RIBOSIDES
SOMATIC CELLS
VIRAL DISEASES
VIRUSES
YEASTS
550201* - Biochemistry- Tracer Techniques