A comparison of the ability of rilpivirine (TMC278) and selected analogues to inhibit clinically relevant HIV-1 reverse transcriptase mutants.
A comparison of the ability of rilpivirine (TMC278) and selected analogues to inhibit clinically relevant HIV-1 reverse transcriptase mutants.
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DOI：
10.1186/1742-4690-9-99
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发表时间：
2012-12-05
期刊：
影响因子：
3.3
通讯作者：
Hughes SH
中科院分区：
文献类型：
--
作者：
Johnson BC;Pauly GT;Rai G;Patel D;Bauman JD;Baker HL;Das K;Schneider JP;Maloney DJ;Arnold E;Thomas CJ;Hughes SH
最近批准的抗艾滋病药物利匹韦林（TMC278，Edurant）是一种非核苷抑制剂（NNRTI），可与逆转录酶（RT）结合并以变构方式阻断 DNA 合成的化学步骤。与早期的 NNRTI 相比，利匹韦林保留了针对特征明确、临床相关的 RT 突变体的效力。专利文献中描述了利匹韦林的许多结构类似物，但其抗病毒活性的详细分析尚未发表。这项工作探讨了其中几种类似物抑制野生型 (WT) 和耐药 HIV-1 复制的能力。我们结合结构活性关系和 X 射线晶体学来检查与利匹韦林结构相关的 NNRTI，以确定它们抑制 WT RT 和几种临床相关 RT 突变体的能力。几种类似物表现出广泛的活性，当受到耐药病毒攻击时，效力仅略有下降。对一些因 RT 突变而效力降低的类似物进行结构分析（晶体学或建模），可以深入了解为什么这些化合物效果较差。化合物之间的细微变化可能导致其活性和耐药性发生巨大差异。具有较大取代基的化合物取代了利匹韦林的嘧啶和苯甲腈基团，从而重新定位口袋残基，往往会失去更多针对我们测试的突变体的活性。这些结果使人们更深入地了解利匹韦林和相关化合物如何与 NNRTI 结合袋相互作用，并有助于新型抑制剂的开发。
The recently approved anti-AIDS drug rilpivirine (TMC278, Edurant) is a nonnucleoside inhibitor (NNRTI) that binds to reverse transcriptase (RT) and allosterically blocks the chemical step of DNA synthesis. In contrast to earlier NNRTIs, rilpivirine retains potency against well-characterized, clinically relevant RT mutants. Many structural analogues of rilpivirine are described in the patent literature, but detailed analyses of their antiviral activities have not been published. This work addresses the ability of several of these analogues to inhibit the replication of wild-type (WT) and drug-resistant HIV-1. We used a combination of structure activity relationships and X-ray crystallography to examine NNRTIs that are structurally related to rilpivirine to determine their ability to inhibit WT RT and several clinically relevant RT mutants. Several analogues showed broad activity with only modest losses of potency when challenged with drug-resistant viruses. Structural analyses (crystallography or modeling) of several analogues whose potencies were reduced by RT mutations provide insight into why these compounds were less effective. Subtle variations between compounds can lead to profound differences in their activities and resistance profiles. Compounds with larger substitutions replacing the pyrimidine and benzonitrile groups of rilpivirine, which reorient pocket residues, tend to lose more activity against the mutants we tested. These results provide a deeper understanding of how rilpivirine and related compounds interact with the NNRTI binding pocket and should facilitate development of novel inhibitors.
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影响因子：
7.3
作者：
Das K;Bauman JD;Rim AS;Dharia C;Clark AD Jr;Camarasa MJ;Balzarini J;Arnold E
通讯作者：
Arnold E
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
7.3
作者：
KELLEY, JL;LINN, JA;SELWAY, JWT
通讯作者：
SELWAY, JWT
影响因子：
168.9
作者：
Lazzarin, Adriano;Campbell, Thomas;Woodfall, Brian
通讯作者：
Woodfall, Brian
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH