在生理浓度的2'-脱氧核苷三磷酸存在的情况下，人类免疫缺陷病毒逆转录酶对受阻DNA链中胸苷酸类似物的差异去除。
Differential removal of thymidine nucleotide analogues from blocked DNA chains by human immunodeficiency virus reverse transcriptase in the presence of physiological concentrations of 2'-deoxynucleoside triphosphates.
作者信息
Meyer P R, Matsuura S E, Schinazi R F, So A G, Scott W A
机构信息
Department of Biochemistry and Molecular Biology, University of Miami, Miami, Florida 33101-6129, USA.
出版信息
Antimicrob Agents Chemother. 2000 Dec;44(12):3465-72. doi: 10.1128/AAC.44.12.3465-3472.2000.
Abstract
Removal of 2',3'-didehydro-3'-deoxythymidine-5'-monophosphate (d4TMP) from a blocked DNA chain can occur through transfer of the chain-terminating residue to a nucleotide acceptor by human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). ATP-dependent removal of either d4TMP or 3'-azido-3'-deoxythymidine-5'-monophosphate (AZTMP) is increased in AZT resistant HIV-1 RT (containing D67N/K70R/T215F/K219Q mutations). Removal of d4TMP is strongly inhibited by the next complementary deoxynucleoside triphosphate (50% inhibitory concentration [IC(50)] of approximately 0.5 microM), whereas removal of AZTMP is much less sensitive to this inhibition (IC(50) of >100 microM). This could explain the lack of cross-resistance by AZT-resistant HIV-1 to d4T in phenotypic drug susceptibility assays.
摘要
从受阻的DNA链上去除2',3'-二脱氢-3'-脱氧胸苷-5'-单磷酸（d4TMP）可通过1型人类免疫缺陷病毒（HIV-1）逆转录酶（RT）将链终止残基转移至核苷酸受体来实现。在对叠氮胸苷（AZT）耐药的HIV-1 RT（含有D67N/K70R/T215F/K219Q突变）中，ATP依赖的d4TMP或3'-叠氮-3'-脱氧胸苷-5'-单磷酸（AZTMP）的去除有所增加。d4TMP的去除受到下一个互补脱氧核苷三磷酸的强烈抑制（50%抑制浓度[IC(50)]约为0.5微摩尔），而AZTMP的去除对这种抑制的敏感性要低得多（IC(50)>100微摩尔）。这可以解释在表型药物敏感性试验中，对AZT耐药的HIV-1对d4T缺乏交叉耐药性的现象。
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