PDF(Pubmed)
Abstract：
Protease inhibitors (PIs) remain an important component of antiretroviral therapy for the treatment of HIV-1 infection due to their high genetic barrier to resistance development. Nevertheless, the two most commonly prescribed HIV PIs, atazanavir and darunavir, still require co-administration with a pharmacokinetic boosting agent to maintain sufficient drug plasma levels which can lead to undesirable drug-drug interactions. Herein, we describe GS-9770, a novel investigational non-peptidomimetic HIV PI with unboosted once-daily oral dosing potential due to improvements in its metabolic stability and its pharmacokinetic properties in preclinical animal species. This compound demonstrates potent inhibitory activity and high on-target selectivity for recombinant HIV-1 protease versus other aspartic proteases tested. In cell culture, GS-9770 inhibits Gag polyprotein cleavage and shows nanomolar anti-HIV-1 potency in primary human cells permissive to HIV-1 infection and against a broad range of HIV subtypes. GS-9770 demonstrates an improved resistance profile against a panel of patient-derived HIV-1 isolates with resistance to atazanavir and darunavir. In resistance selection experiments, GS-9770 prevented the emergence of breakthrough HIV-1 variants at all fixed drug concentrations tested and required multiple protease substitutions to enable outgrowth of virus exposed to escalating concentrations of GS-9770. This compound also remained fully active against viruses resistant to drugs from other antiviral classes and showed no in vitro antagonism when combined pairwise with drugs from other antiretroviral classes. Collectively, these preclinical data identify GS-9770 as a potent, non-peptidomimetic once-daily oral HIV PI with potential to overcome the persistent requirement for pharmacological boosting with this class of antiretroviral agents.
摘要：
蛋白酶抑制剂（PI）仍然是抗逆转录病毒疗法治疗HIV-1感染的重要组成部分，因为它们对耐药性发展具有很高的遗传障碍。然而，两种最常用的HIVPIs，阿扎那韦和达鲁那韦,仍然需要与药代动力学促进剂共同给药以维持足够的药物血浆水平，这可能导致不期望的药物-药物相互作用。在这里，我们描述了GS-9770,这是一种新型的研究性非拟肽HIVPI,由于其在临床前动物物种中的代谢稳定性和药代动力学特性得到改善,因此具有每日一次口服给药潜力。与测试的其他天冬氨酸蛋白酶相比,该化合物对重组HIV-1蛋白酶表现出有效的抑制活性和高的靶向选择性。在细胞培养中,GS-9770抑制Gag多蛋白裂解，并在允许HIV-1感染和抵抗广泛HIV亚型的原代人细胞中显示纳摩尔抗HIV-1效力。GS-9770对一组对阿扎那韦和达鲁那韦具有抗性的患者来源的HIV-1分离株具有改进的抗性谱。在抗性选择实验中，GS-9770在所有测试的固定药物浓度下防止突破性HIV-1变体的出现，并且需要多个蛋白酶替换，以使暴露于不断升高的GS-9770浓度的病毒能够生长。该化合物还对对来自其他抗病毒类别的药物具有抗性的病毒保持完全活性,并且当与来自其他抗逆转录病毒类别的药物成对组合时没有显示体外拮抗作用。总的来说，这些临床前数据表明GS-9770是一种有效的，每天口服一次的非肽模拟物HIVPI，有可能克服此类抗逆转录病毒药物对药理增强的持续需求。
