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1-[(2-羟基乙氧基)甲基]-6-(苯硫基)胸腺嘧啶衍生物对不同1型人类免疫缺陷病毒突变株的差异活性

Differential activities of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives against different human immunodeficiency virus type 1 mutant strains.

作者信息

Balzarini J, Baba M, De Clercq E

机构信息

Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.

出版信息

Antimicrob Agents Chemother. 1995 Apr;39(4):998-1002. doi: 10.1128/AAC.39.4.998.

DOI:10.1128/AAC.39.4.998
PMID:7540384
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC162671/
Abstract

A series of 23 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives that were highly potent inhibitors of wild-type human immunodeficiency virus type 1 strain IIIB (HIV-1/IIIB) replication in CEM cells were evaluated against a panel of HIV-1 mutant strains containing the replacement of leucine by isoleucine at position 100 (100-Leu-->Ile), 103-Lys-->Asn, 106-Val-->Ala, 138-Glu-->Lys, 181-Tyr-->Cys, 181-Tyr-->Ile, or 188-Tyr-->His in their reverse transcriptase (RT). A different structure-antiviral activity relationship was found, depending on the nature of the mutated amino acid in the HIV-1 RT. The results show that 5-ethyl-1-ethoxymethyl-6-(3,5-dimethylbenzyl)uracil, 5-ethyl-1-ethoxymethyl-6-(3,5-dimethylphenylthio)uracil, and 5-ethyl-1-ethoxymethyl-6-(3,5-dimethylphenylthio)-2-thiouracil remain active against the majority of viruses containing single mutations which confer resistance to nonnucleoside RT inhibitors.

摘要

对一系列23种1-[(2-羟基乙氧基)甲基]-6-(苯硫基)胸腺嘧啶衍生物进行了评估，这些衍生物是野生型人类免疫缺陷病毒1型IIIB株（HIV-1/IIIB）在CEM细胞中复制的高效抑制剂，评估对象为一组HIV-1突变株，这些突变株的逆转录酶（RT）中第100位的亮氨酸被异亮氨酸取代（100-Leu→Ile）、第103位的赖氨酸被天冬酰胺取代、第106位的缬氨酸被丙氨酸取代、第138位的谷氨酸被赖氨酸取代、第181位的酪氨酸被半胱氨酸取代、第181位的酪氨酸被异亮氨酸取代或第188位的酪氨酸被组氨酸取代。根据HIV-1 RT中突变氨基酸的性质，发现了不同的结构-抗病毒活性关系。结果表明，5-乙基-1-乙氧基甲基-6-(3,5-二甲基苄基)尿嘧啶、5-乙基-1-乙氧基甲基-6-(3,5-二甲基苯硫基)尿嘧啶和5-乙基-1-乙氧基甲基-6-(3,5-二甲基苯硫基)-2-硫尿嘧啶对大多数含有导致对非核苷RT抑制剂产生抗性的单一突变的病毒仍具有活性。

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