TMC114, a novel human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including a broad range of clinical isolates
TMC114, a novel human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including a broad range of clinical isolates
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DOI：
10.1128/aac.49.6.2314-2321.2005
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发表时间：
2005-06-01
影响因子：
4.9
通讯作者：
de Béthune, MP
中科院分区：
文献类型：
--
作者：
De Meyer, S;Azijn, H;de Béthune, MP
本研究的目的是表征TMC 114的抗病毒活性、细胞毒性和作用机制，TMC 114是一种新型的人类免疫缺陷病毒1型（HIV-1）蛋白酶抑制剂（PI）。TMC 114具有强效抗HIV活性，50%有效浓度（EC 50）为1 - 5 nM，90%有效浓度为2.7 - 13 nM。TMC 114在高达100 μ M的浓度下没有表现出细胞毒性（选择性指数，> 20，000）。携带多种蛋白酶突变并对平均5种其他PI表现出抗性的19种重组临床分离株中的所有病毒均对TMC 114敏感，定义为EC 50的倍数变化< 4。TMC 114对来自最近临床样本的1，501种PI耐药重组病毒中的大多数也有效，75%的样本EC（50）< 10 nM。在使用HIV-1 LAI的连续传代实验中，选择了两个突变（R41 T和K70 E）。一种选定的病毒显示对TMC 114的敏感性降低10倍，但对当前PI的敏感性降低< 10倍（未评估阿扎那韦），沙奎那韦除外。然而，当通过定点诱变将选定的突变引入实验室菌株时，它们对TMC 114或其他PI的敏感性没有影响。没有证据表明TMC 114与任何现有PI或逆转录酶抑制剂之间存在拮抗作用。与利托那韦、奈非那韦和安普那韦的组合显示出一些协同作用的证据。这些结果表明，TMC 114是一个潜在的候选人治疗的幼稚和PI经验丰富的艾滋病毒患者。
The purpose of this study was to characterize the antiviral activity, cytotoxicity, and mechanism of action of TMC114, a novel human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI). TMC114 exhibited potent anti-HIV activity with a 50% effective concentration (EC50) of 1 to 5 nM and a 90% effective concentration of 2.7 to 13 nM. TMC114 exhibited no cytotoxicity at concentrations up to 100 mu M (selectivity index, > 20,000). All viruses in a panel of 19 recombinant clinical isolates carrying multiple protease mutations and demonstrating resistance to an average of five other PIs, were susceptible to TMC114, defined as a fold change in EC50 of < 4. TMC114 was also effective against the majority of 1,501 PI-resistant recombinant viruses derived from recent clinical samples, with EC(50)s of < 10 nM for 75% of the samples. In sequential passage experiments using HIV-1 LAI, two mutations (R41T and K70E) were selected. One selected virus showed a 10-fold reduction in susceptibility to TMC114, but < 10-fold reductions in susceptibility to the current PIs (atazanavir was not assessed), except saquinavir. However, when the selected mutations were introduced into a laboratory strain by site-directed mutagenesis, they had no effect on susceptibility to TMC114 or other PIs. There was no evidence of antagonism between TMC114 and any currently available PIs or reverse transcriptase inhibitors. Combinations with ritonavir, nelfinavir, and amprenavir showed some evidence of synergy. These results suggest that TMC114 is a potential candidate for the treatment of both naive and PI-experienced patients with HIV.