Development of non-nucleoside human immunodeficiency virus type 1 (HIV-1) inhibitor which is active against HIV-1 viruses resistant to BI-RG-587 and to TIBO R82150 (Meeting abstract).

Important note: Information in this article was accurate in 1993. The state of the art may have changed since the publication date.

Development of non-nucleoside human immunodeficiency virus type 1 (HIV-1) inhibitor which is active against HIV-1 viruses resistant to BI-RG-587 and to TIBO R82150 (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 34:A1670 1993. Unique Identifier : AIDSLINE ICDB/93692611
Piras G; Chu SH; Dutschman GE; Im GJ; Pan BC; Chen ZH; Cheng YC; Yale Univ., New Haven, CT

Abstract: 5-Ethyl-1-benzyloxymethyl-6-(alpha-pyridylseleno)uracil (E-BEPYSU), an analogue of 5-ethyl-1-benzyloxymethyl-6-(phenylthio)uracil (E-BPU) has been synthesized. It targets the reverse transcriptase enzyme inhibiting both the associated RNA- and DNA-dependent polymerase activities. It is a noncompetitive inhibitor with deoxynucleoside triphosphates (dNTPs), Poly(rA)-oligo(dT)10 and uncompetitive with Poly(rC)-oligo(dG) 12-18 and Poly(dC)-oligo(dG)12-18. It is also active against TIBO-resistant RT (Leu 100----Ile) and BI-RG-587 resistant RT (Tyr 181----Cys) with Iso shifted, respectively, 3- and 35-fold. With TIBO- or BI-RG-587-resistant HIV-l viruses, E-BEPYSU requires higher doses than those used to inhibit the parental virus, however it is still effective at concentrations which are, respectively, 19-fold and 25-fold lower than cytotoxic dose. In addition, it is more soluble than E-BPU. This new E-BEPYSU derivative should be considered a promising candidate for treatment of non-nucleoside resistant mutants of HIV-1.

Keywords: Amino Acid Sequence Animal Antiviral Agents/THERAPEUTIC USE Benzodiazepines/*THERAPEUTIC USE Drug Resistance DNA Polymerases/*METABOLISM HIV Infections/*DRUG THERAPY HIV-1/*METABOLISM Imidazoles/*THERAPEUTIC USE Pyridines/*THERAPEUTIC USE RNA Polymerases/METABOLISM RNA-Directed DNA Polymerase/ANTAGONISTS & INHIB Uracil/*METABOLISM ABSTRACT
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M9370992

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