Biochemical Studies on the Mechanism of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Resistance to 1-(β-d-Dioxolane)Thymine Triphosphate
Biochemical Studies on the Mechanism of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Resistance to 1-(β-d-Dioxolane)Thymine Triphosphate
复制标题
人类免疫缺陷病毒1型逆转录酶抗1-(β-d-二氧戊环)胸腺嘧啶三磷酸机制的生化研究
DOI：
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发表时间：
2007
影响因子：
4.9
通讯作者：
R. Schinazi
中科院分区：
文献类型：
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作者：
J. Lennerstrand;C. K. Chu;R. Schinazi
摘要利用大量的人类免疫缺陷病毒1型逆转录酶（RT）耐药突变株，研究其对1-（β-d-二氧戊环）胸腺嘧啶三磷酸（DOT-TP）等核苷酸类似物的耐药机制。含有胸苷类似物相关突变（TAM）的RT或含有T69 S-SG插入的RT与TAM组合通过ATP介导的焦磷酸解作用从链终止的DNA引物/模板中去除3′-叠氮基-3 ′-脱氧胸苷-5 ′-单磷酸或替诺福韦的效率高于DOT-单磷酸。对于DOT-TP的非ATP依赖性歧视，发现具有家族突变的Q151 M突变的RT具有高水平的抗性，而仅具有M184 V或Y115 F突变的RT不赋予DOT-TP抗性。一个较低程度的耐药DOT-TP比替诺福韦二磷酸或碳病毒-TP被发现RT含有K65 R突变。在目前的研究中，1-（β-d-二氧戊环）鸟嘌呤三磷酸，另一种具有二氧戊环糖部分的核苷酸，显示出与DOT-TP相似的耐药性。结果表明，与其他批准的核苷类似物相比，DOT对TAM、M184 V和K65 R等突变的适应性更强，这些突变通常存在于来自多核苷治疗失败的受试者的病毒中。
ABSTRACT A large panel of drug-resistant mutants of human immunodeficiency virus type 1 reverse transcriptase (RT) was used to study the mechanisms of resistance to 1-(β-d-dioxolane)thymine triphosphate (DOT-TP) and other nucleotide analogs. RT containing thymidine analog-associated mutations (TAM) or RT with a T69S-SG insertion in combination with TAM removed 3′-azido-3′-deoxythymidine-5′-monophosphate or tenofovir more efficiently than DOT-monophosphate from chain-terminated DNA primer/template through ATP-mediated pyrophosphorolysis. For non-ATP-dependent discrimination toward DOT-TP, high levels of resistance were found for RT bearing the Q151M mutation with family mutations, while RT bearing only the M184V or the Y115F mutation conferred no resistance to DOT-TP. A lower degree of resistance to DOT-TP than to tenofovir diphosphate or carbovir-TP was found for RT containing the K65R mutation. In the present studies, 1-(β-d-dioxolane)guanine triphosphate, another nucleotide with a dioxolane sugar moiety, showed a resistance profile similar to that of DOT-TP. The results suggest that DOT, compared with other approved nucleoside analogs, is overall more resilient to mutations such as TAM, M184V, and K65R, which are commonly found in viruses derived from subjects failing multinucleoside therapy.
使用瞬态动力学分析探讨 HIV-1 逆转录酶介导的 AZT 耐药的分子机制。
DOI：
10.1021/bi034435l
发表时间：
2003
期刊：
Biochemistry.
影响因子：
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作者：
Ray,AdrianS;Murakami,Eisuke;Basavapathruni,Aravind;Vaccaro,JosephA;Ulrich,Dagny;Chu,ChungK;Schinazi,RaymondF;Anderson,KarenS
通讯作者：
Anderson,KarenS
影响因子：
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作者：
A. Wensing;Vincent Calvez;F. Ceccherini‐Silberstein;Charlotte Charpentier;H. Günthard;R. Paredes;Robert W. Shafer;D. Richman
通讯作者：
A. Wensing;Vincent Calvez;F. Ceccherini‐Silberstein;Charlotte Charpentier;H. Günthard;R. Paredes;Robert W. Shafer;D. Richman