Potent and selective inhibition of human immunodeficiency virus type 1 (HIV-1) by 5-ethyl-6-phenylthiouracil derivatives through their interaction with the HIV-1 reverse transcriptase.

Baba, Masanori; Clercq, Erik De; Tanaka, Hiromichi; Ubasawa, Masaru; Takashima, Hideaki; Sekiya, Kouichi; Nitta, Issei; Umezu, Kohei; Nakashima, Hideki; Mori, Shuichi

doi:10.1073/pnas.88.6.2356

Cited by 165 publications

(109 citation statements)

References 26 publications

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“…However, for HEPT itself, which is a relatively weak inhibitor of HIV-1 RT, we found a competitive type of inhibition (Debyser et al, 1992a). RT inhibition by E-EPU was found to be non-competitive with respect to dGTP but competitive with respect to dTTP (Baba et al, 1991). Here, we show that the relatively weak inhibition of SIVagm3 by TIBO is also competitive with respect to the substrate.…”

Section: Discussionmentioning

confidence: 49%

“…For HEPT and its derivative E-EPU [5-ethyl-l-ethoxymethyl-6-(phenylthio)uracil] (Fig. 1), see Miyasaka et aL (1989) and Baba et aL (1991). Stock solutions of all compounds were prepared in DMSO.…”

Section: Methodsmentioning

confidence: 99%

“…We have now studied various SIV strains for their susceptibility to inhibition by the novel HIV-l-specific reverse transcriptase (RT) inhibitors tetrahydro-imidazo [4,5, l-jk][ 1,4]-benzodiazepin-2(1H)-one and -thione (TIBO) and the 1-(2-hydroxyethoxymethyl)-6-(phenylthio)-thymine (HEPT) derivatives (Pauwels et al, 1990;Baba et al, 1991 ;Debyser et al, 1991). In contrast to the classical RT inhibitors such as phosphonoformic acid (PFA) and 3'-azido-3'-deoxythymidine (AZT) 5'-triphosphate, TIBO and HEPT inhibit HIV-1 RT, but not HIV-2 RT.…”

Section: Introductionmentioning

confidence: 99%

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Differential inhibitory effects of TIBO derivatives on different strains of simian immunodeficiency virus

Debyser

Vreese

Pauwels

et al. 1992

Journal of General Virology

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Section: Discussionmentioning

confidence: 49%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Differential inhibitory effects of TIBO derivatives on different strains of simian immunodeficiency virus

Debyser

Vreese

Pauwels

et al. 1992

Journal of General Virology

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“…(For reviews, see Oberg, 1988;De Clercq, 1991Hammer, 1992a, 1992b). Several non-nucleoside inhibitors acting directly on HIV-1 RT have recently been found (Pauwels et al, 1990;Merluzzi et al, 1990;Goldman et al, 1991;Baba et al, 1991;Romero et aI., 1991;Camarasa et el., 1992). These non-nucleoside inhibitors seem to cause a more rapid resistance development than the nucleoside analogues which inhibit HIV RT after intracellular phosphorylation to triphosphates (Smith et el., 1987;Larder et al, 1989aLarder et al, , 1989bLarder et al, , 1991Richman et el., 1991;Nunberg et aI., 1991;Mellors et al, 1992;St.…”

Section: Introductionmentioning

confidence: 99%

Characterization of HIV Reverse Transcriptases with Tyr181→Cys and Leu100→lle Mutations

Zhang

Vrang

Unge

et al. 1993

Antivir Chem Chemother

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SummaryTwo mutants of human immunodeficiency virus (HIV) reverse transcriptase (RT), Tyr181 to Cys and Leu100 to lie, have been prepared and characterized by use of various inhibitors. As compared to~~type RT the mutant RT's had lower KeatlK m values. The K m values were lower with heteropolymeric than with homopoIymeric template-primers. Inhibition by phosphonoformate was of mixed type with both wild-type and mutant RT's and the mutants were less sensitive to phosphonoformate than the wild type RT. The nonnucleoside RT inhibitors 9-CI-TIBO and L-697,661 gave a non-competitive inhibition with respect to substrate of the wild type RT. The mutant RT's were inhibited at higher concentrations, showing a mixed type of inhibition with respect to substrate. ddGTP caused a competitive inhibition of wild type and mutant RT's with respect to substrate, RT preparations with different mutations are useful in rapidly characterizing the interaction between various inhibitors and HIV RT and thus facilitate the development of new inhibitors.

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“…These include tetrahydroimidazo- [4,5,1-jk] derivatives (1,3,14), nevirapine (13), pyridinone derivatives (7), ƒ¿-anilinophenylacetamide (a-APA) derivatives (17), and thiadiazol derivatives (8). These compounds act as highly potent and specific inhibitors of HIV-1 RT without requiring intracellular metabolism (5).…”

mentioning

confidence: 99%

Different Properties of Wild Type and Drug‐Resistant Mutants of Human Immunodeficiency Virus Type 1 Reverse Transcriptase In Vitro

Ijichi¹,

Fujiwara²,

Shigeta

et al. 1996

Microbiology and Immunology

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Drug-resistant mutants of human immunodeficiency virus type 1 (HIV-1) emerge during treatment with various reverse transcriptase (RT) inhibitors in vitro and in vivo. However, the virological nature and pathogenic importance of these mutants have not been fully elucidated. In this study, we have examined HIV-1 mutants resistant to 3 `-azido-3 cdeoxythymidine (AZT) and nonnucleoside RT inhibitors (NNRTIs) for their infectivity, RT activity, and replication in MT-4 cells. Although the infectivity of AZT-and NNRTIresistant mutants was similar, the RT activity of AZT-resistant mutants was much higher than that of NNRTI-resistant mutants and their wild types. Furthermore, the RT activity of NNRTI-resistant mutants was significantly lower than that of the wild types. In contrast, the replication of NNRTI-resistant mutants was found to be greater than that of AZT-resistant mutants and the wild types. When HIV-1 proviral DNA (cDNA) synthesis was examined by PCR in MT-4 cells infected with the wild type, AZT-resistant mutant, or NNRTI-resistant mutant, the PCR signal of the NNRTI-resistant mutant was found to be much higher than those of the wild type and AZT-resistant mutant. These results suggest that the drug-resistant mutants differ from their corresponding wild types not only in drug sensitivity but also in other virological properties.

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Potent and selective inhibition of human immunodeficiency virus type 1 (HIV-1) by 5-ethyl-6-phenylthiouracil derivatives through their interaction with the HIV-1 reverse transcriptase.

Abstract: In the search for 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine (HEPT) derivatives, we have found several 5-ethyl-6-(phenylthio)uracil analogues to be highly potent and selective inhibitors of human immunodeficiency virus (HIV) type 1.

Cited by 165 publications

References 26 publications

Differential inhibitory effects of TIBO derivatives on different strains of simian immunodeficiency virus

Differential inhibitory effects of TIBO derivatives on different strains of simian immunodeficiency virus

Characterization of HIV Reverse Transcriptases with Tyr181→Cys and Leu100→lle Mutations

Different Properties of Wild Type and Drug‐Resistant Mutants of Human Immunodeficiency Virus Type 1 Reverse Transcriptase In Vitro

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