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首页> 外文期刊>Antimicrobial agents and chemotherapy. >In Vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor.
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In Vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor.

机译：下一代HIV整合酶抑制剂S / GSK1349572的体外抗逆转录病毒特性。

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S/GSK1349572 is a next-generation HIV integrase (IN) inhibitor designed to deliver potent antiviral activity with a low-milligram once-daily dose requiring no pharmacokinetic (PK) booster. In addition, S/GSK1349572 demonstrates activity against clinically relevant IN mutant viruses and has potential for a high genetic barrier to resistance. S/GSK1349572 is a two-metal-binding HIV integrase strand transfer inhibitor whose mechanism of action was established through in vitro integrase enzyme assays, resistance passage experiments, activity against viral strains resistant to other classes of anti-HIV agents, and mechanistic cellular assays. In a variety of cellular antiviral assays, S/GSK1349572 inhibited HIV replication with low-nanomolar or subnanomolar potency and with a selectivity index of 9,400. The protein-adjusted half-maximal effective concentration (PA-EC(50)) extrapolated to 100% human serum was 38 nM. When virus was passaged in the presence of S/GSK1349572, highly resistant mutants were not selected, but mutations that effected a low fold change (FC) in the EC(50) (up to 4.1 fold) were identified in the vicinity of the integrase active site. S/GSK1349572 demonstrated activity against site-directed molecular clones containing the raltegravir-resistant signature mutations Y143R, Q148K, N155H, and G140S/Q148H (FCs, 1.4, 1.1, 1.2, and 2.6, respectively), while these mutants led to a high FC in the EC(50) of raltegravir (11- to >130-fold). Either additive or synergistic effects were observed when S/GSK1349572 was tested in combination with representative approved antiretroviral agents; no antagonistic effects were seen. These findings demonstrate that S/GSK1349572 would be classified as a next-generation drug in the integrase inhibitor class, with a resistance profile markedly different from that of first-generation integrase inhibitors.
机译：S / GSK1349572是下一代HIV整合酶（IN）抑制剂，旨在以低毫克的每日一次剂量提供有效的抗病毒活性，而无需药代动力学（PK）增强剂。另外，S / GSK1349572表现出针对临床相关的IN突变病毒的活性，并具有抗药性的高遗传屏障的潜力。 S / GSK1349572是两种金属结合的HIV整合酶链转移抑制剂，其作用机理是通过体外整合酶测定，耐药性传代实验，针对对其他类型的抗HIV试剂耐药的病毒株的活性以及机械细胞测定法建立的。在多种细胞抗病毒测定中，S / GSK1349572以低纳摩尔或亚纳摩尔效价和9,400的选择性指数抑制HIV复制。外推到100％人血清的蛋白质调整的半数最大有效浓度（PA-EC（50））为38 nM。当在S / GSK1349572存在的情况下传播病毒时，未选择高抗性突变体，但在整合酶附近鉴定出在EC（50）中引起低倍变化（FC）的突变（最高4.1倍）。活动站点。 S / GSK1349572展示了对定点分子克隆的活性，该分子克隆包含耐拉格韦的签名突变Y143R，Q148K，N155H和G140S / Q148H（分别为FC，1.4、1.1、1.2和2.6），而这些突变导致高raltegravir EC（50）中的FC（11到> 130倍）。当将S / GSK1349572与代表性的认可抗逆转录病毒药物联合测试时，观察到加性或协同作用。没有看到拮抗作用。这些发现表明，S / GSK1349572将被归类为整合酶抑制剂类别中的下一代药物，其耐药性与第一代整合酶抑制剂明显不同。

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