Urano Emiko, Miyauchi Kosuke, Kojima Yoko, Hamatake Makiko, Ablan Sherimay D, Fudo Satoshi, Freed Eric O, Hoshino Tyuji, Komano Jun
AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan.
The Virus-Cell Interaction Section, HIV Dynamics and Replication Program, National Cancer Institute, Frederick, MD, 21701, USA.
ChemMedChem. 2016 Oct 19;11(20):2320-2326. doi: 10.1002/cmdc.201600375. Epub 2016 Sep 16.
A novel HIV-1 inhibitor, 6-(tert-butyl)-4-phenyl-4-(trifluoromethyl)-1H,3H-1,3,5-triazin-2-one (compound 1), was identified from a compound library screened for the ability to inhibit HIV-1 replication. EC values of compound 1 were found to range from 107.9 to 145.4 nm against primary HIV-1 clinical isolates. In in vitro assays, HIV-1 reverse transcriptase (RT) activity was inhibited by compound 1 with an EC of 4.3 μm. An assay for resistance to compound 1 selected a variant of HIV-1 with a RT mutation (RT ); this frequently identified mutation confers mild resistance to non-nucleoside RT inhibitors (NNRTIs). A recombinant HIV-1 bearing RT exhibited a 41-fold greater resistance to compound 1 than the wild-type virus. Compound 1 was also effective against HIV-1 with RT , one of the major mutations that confers substantial resistance to NNRTIs. Computer-assisted docking simulations indicated that compound 1 binds to the RT NNRTI binding pocket in a manner similar to that of efavirenz; however, the putative compound 1 binding site is located further from RT than that of efavirenz. Compound 1 is a novel NNRTI with a unique drug-resistance profile.
一种新型HIV-1抑制剂，6-(叔丁基)-4-苯基-4-(三氟甲基)-1H,3H-1,3,5-三嗪-2-酮（化合物1），是从一个针对抑制HIV-1复制能力筛选的化合物库中鉴定出来的。发现化合物1对原发性HIV-1临床分离株的EC值范围为107.9至145.4 nm。在体外试验中，化合物1抑制HIV-1逆转录酶（RT）活性，其EC为4.3 μm。对化合物1的耐药性检测筛选出一种带有RT突变（RT ）的HIV-1变体；这种经常鉴定出的突变赋予对非核苷类逆转录酶抑制剂（NNRTIs）的轻度耐药性。携带RT的重组HIV-1对化合物1的耐药性比野生型病毒高41倍。化合物1对带有RT 的HIV-1也有效，RT 是赋予对NNRTIs显著耐药性的主要突变之一。计算机辅助对接模拟表明，化合物1以类似于依非韦伦的方式结合到RT的NNRTI结合口袋中；然而，推测的化合物1结合位点比依非韦伦的结合位点离RT更远。化合物1是一种具有独特耐药谱的新型NNRTI。
