Oxathiin carboxanilide, a potent inhibitor of human immunodeficiency virus reproduction.
Oxathiin carboxanilide (OC), NSC 615985, a compound originally synthesized as a potential fungicide, was demonstrated to be highly active in preventing human immunodeficiency virus (HIV)-induced cell killing and in inhibiting HIV reproduction. Virus-infected CD4+ lymphocytes were completely protected by 0.5 microM OC, whereas no toxicity was observed at concentrations below 50 microM OC. Production of infectious virus, viral p24 antigen, and virion reverse transcriptase were reduced by OC at concentrations that prevented viral cell killing. A variety of CD4+ T-cell lines were protected by OC from HIV cytopathicity, and OC inhibited two distinct strains of HIV-1. However, HIV-2 infections were unaffected by OC. OC had no direct effect on virions of HIV or on the enzymatic activities of HIV reverse transcriptase or HIV protease. Time-limited treatments of cells with OC before, during, or after exposure of cells to virus failed to protect cells from the eventual cytopathic effects of HIV, and OC failed to inhibit the production of virus from cells in which infection was established or from chronically infected cells. We conclude that the highly active OC has a reversible effect on some early stage of HIV-1 reproduction and cytopathicity. Pilot in vivo experiments showed that circulating concentrations of OC exceeding 1 microM could be achieved and sustained in hamsters for at least a week with no remarkable toxicological sequelae. OC represents a new class of anti-HIV agents that are promising candidates for drug development.
Bader
J P
JP
Division of Cancer Treatment, National Cancer Institute, Bethesda, MD 20892.
McMahon
J B
JB
Schultz
R J
RJ
Narayanan
V L
VL
Pierce
J B
JB
Harrison
W A
WA
Weislow
O S
OS
Midelfort
C F
CF
Stinson
S F
SF
Boyd
M R
MR
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D015704:CD4 Antigens / Q000032:analysis; D002261:Carboxin / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D006224:Cricetinae; D004353:Drug Evaluation, Preclinical; D017320:HIV Protease Inhibitors; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D006801:Humans; D018894:Reverse Transcriptase Inhibitors; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D015704:CD4 Antigens; D017320:HIV Protease Inhibitors; C070134:NSC 615985; D018894:Reverse Transcriptase Inhibitors; D002261:Carboxin