The HEPT Analogue WPR-6 Is Active against a Broad Spectrum of Nonnucleoside Reverse Transcriptase Drug-Resistant HIV-1 Strains of Different Serotypes
The HEPT Analogue WPR-6 Is Active against a Broad Spectrum of Nonnucleoside Reverse Transcriptase Drug-Resistant HIV-1 Strains of Different Serotypes
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HEPT 类似物 WPR-6 对不同血清型的多种非核苷逆转录酶耐药 HIV-1 菌株具有活性
DOI：
10.1128/aac.00440-15
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发表时间：
2015-06
影响因子：
4.9
通讯作者：
Ma L
中科院分区：
文献类型：
--
作者：
Jiang S;Shao Y;Wang X;Ma L
非核苷类逆转录酶抑制剂（NNRTIs）是高效抗逆转录病毒治疗（HAART）的重要组成部分，用于治疗人类免疫缺陷病毒1型（HIV-1）。然而，由于耐药性的出现和目前抗HIV药物的不良反应，开发具有优异安全性、改善对NNRTI耐药病毒的活性以及增强对不同亚型临床分离株的活性的新型NNRTI是至关重要的。在这里，我们确定了1-[苄氧基甲基]-6-（3，5-二甲基苄基）-5-碘嘧啶-2，4（1H，3 H）-二酮（WPR-6），一种新的NNRTI，对实验室适应的HIV-1菌株SF 33的50%有效浓度（EC 50）为2至4 nM，对核苷逆转录酶抑制剂耐药HIV-1的EC 50为7至14 nM。1株7391，治疗指数>1 × 104。一组主要在中国流行的不同亚型的五种代表性临床病毒分离株对WPR-6高度敏感，EC 50范围为1至6 nM。此外，WPR-6对含有K103 N和Y181 C突变的最流行的NNRTI耐药病毒显示出优异的抗病毒效力。为了确定WPR-6是否选择新的抗性突变体，在MT-4细胞上用实验室适应的HIV-1菌株SF 33进行体外抗性选择。结果表明，V106 I和Y188 L是在突破性病毒中检测到的两种主要NNRTI相关耐药突变。综上所述，这些体外数据表明，WPR-6对HIV-1的疗效高于参考HEPT类似物TNK 651和市售药物奈韦拉平。然而，要将其开发为新的NNRTI，需要进一步改进其药理学性质。
ABSTRACT Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are important components of the highly active antiretroviral therapy (HAART) used to treat human immunodeficiency type 1 virus (HIV-1). However, because of the emergence of drug resistance and the adverse effects of current anti-HIV drugs, it is essential to develop novel NNRTIs with an excellent safety profile, improved activity against NNRTI-resistant viruses, and enhanced activity against clinical isolates of different subtypes. Here, we have identified 1-[(benzyloxy)methyl]-6-(3,5-dimethylbenzyl)-5-iodopyrimidine-2,4(1H,3H)-dione (WPR-6), a novel NNRTI with a 50% effective concentration (EC50) of 2 to 4 nM against laboratory-adapted HIV-1 strain SF33 and an EC50 of 7 to 14 nM against nucleoside reverse transcriptase inhibitor-resistant HIV-1 strain 7391 with a therapeutic index of >1 × 104. A panel of five representative clinical virus isolates of different subtypes circulating predominantly in China was highly sensitive to WPR-6, with EC50s ranging from 1 to 6 nM. In addition, WPR-6 showed excellent antiviral potency against the most prevalent NNRTI-resistant viruses containing the K103N and Y181C mutations. To determine whether WPR-6 selects for novel resistant mutants, in vitro resistance selection was conducted with laboratory-adapted HIV-1 strain SF33 on MT-4 cells. The results demonstrated that V106I and Y188L were the two dominant NNRTI-associated resistance mutations detected in the breakthrough viruses. Taken together, these in vitro data indicate that WPR-6 has greater efficacy than the reference HEPT analogue TNK651 and the marketed drug nevirapine against HIV-1. However, to develop it as a new NNRTI, further improvement of its pharmacological properties is warranted.
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影响因子：
3.7
作者：
Sax PE;Sypek A;Berkowitz BK;Morris BL;Losina E;Paltiel AD;Kelly KA;Seage GR 3rd;Walensky RP;Weinstein MC;Eron J;Freedberg KA
通讯作者：
Freedberg KA
ART可以防止MSM之间的HIV传播吗？
DOI：
10.1097/qad.0b013e328355713d
发表时间：
2012-11-28
期刊：
AIDS (London, England)
影响因子：
--
作者：
Muessig KE;Smith MK;Powers KA;Lo YR;Burns DN;Grulich AE;Phillips AN;Cohen MS
通讯作者：
Cohen MS
两个 M-T 钩残基大大提高了 HIV-1 融合抑制剂 SC29EK 的抗病毒活性和耐药性
影响因子：
3.3
作者：
Chong H;Qiu Z;Sun J;Qiao Y;Li X;He Y
通讯作者：
He Y
影响因子：
5.7
作者：
A. Milinkovic;E. Martinez
通讯作者：
A. Milinkovic;E. Martinez
影响因子：
14.8
作者：
van 't Wout, Angelique B.;Schuitemaker, Hanneke;Kootstra, Neeltje A.
通讯作者：
Kootstra, Neeltje A.