In Vitro Characterization of GS-8374, a Novel Phosphonate-Containing Inhibitor of HIV-1 Protease with a Favorable Resistance Profile
In Vitro Characterization of GS-8374, a Novel Phosphonate-Containing Inhibitor of HIV-1 Protease with a Favorable Resistance Profile
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DOI：
10.1128/aac.01183-10
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发表时间：
2011-04-01
影响因子：
4.9
通讯作者：
Cihlar, Tomas
中科院分区：
文献类型：
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作者：
Callebaut, Christian;Stray, Kirsten;Cihlar, Tomas
GS-8374是一种新型的双四氢呋喃HIV-1蛋白酶(PR)抑制剂，具有独特的二乙基膦酸基。它选自一系列类似物，其含有通过连接物连接到P-1苯环的对位的各种二(烷基)膦酸基取代基。GS-8374对HIV-1PR具有高效抑制作用(K(I)=8.1pM)，对宿主蛋白水解酶无明显影响。GS-8374与PR结合的动力学和热力学分析表明，缓蚀剂的失活速度非常慢，而焓和熵对总自由结合能的贡献是有利的。GS-8374在T细胞系、原代CD4(+)T细胞(50%有效浓度左垂向EC(50)右垂=3.4~11.5 nM)和巨噬细胞(EC(50)=25.5 nM)中显示出较强的抗逆转录病毒活性，并在多种人类细胞类型中表现出较低的细胞毒性。GS-8374的抗病毒效力仅受人血清蛋白结合的适度影响，它与多种批准的抗逆转录病毒药物联合显示出协同作用。当对一组具有高水平PI耐药性的24例患者来源的病毒进行表观检测时，GS-8374显示出比任何临床批准的PI更低的EC(50)S和更低的倍数耐药性。与其他PI类似，利托那韦在体外可有效阻断GS-8374的肝微粒体代谢，提示在体内有有效的药代动力学促进作用。综上所述，这一广泛的体外药理分析结果表明，GS-8374是一个很有希望的候选药物，可以作为一种新的抗逆转录病毒药物进行进一步评估，对治疗初学者和有经验的患者都有潜在的临床疗效。
GS-8374 is a novel bis-tetrahydrofuran HIV-1 protease (PR) inhibitor (PI) with a unique diethylphosphonate moiety. It was selected from a series of analogs containing various di(alkyl)phosphonate substitutions connected via a linker to the para position of a P-1 phenyl ring. GS-8374 inhibits HIV-1 PR with high potency (K(i) = 8.1 pM) and with no known effect on host proteases. Kinetic and thermodynamic analysis of GS-8374 binding to PR demonstrated an extremely slow off rate for the inhibitor and favorable contributions of both the enthalpic and entropic components to the total free binding energy. GS-8374 showed potent antiretroviral activity in T-cell lines, primary CD4(+) T cells (50% effective concentration left perpendicularEC(50)right perpendicular = 3.4 to 11.5 nM), and macrophages (EC(50) = 25.5 nM) and exhibited low cytotoxicity in multiple human cell types. The antiviral potency of GS-8374 was only moderately affected by human serum protein binding, and its combination with multiple approved antiretrovirals showed synergistic effects. When it was tested in a PhenoSense assay against a panel of 24 patient-derived viruses with high-level PI resistance, GS-8374 showed lower mean EC(50)s and lower fold resistance than any of the clinically approved PIs. Similar to other PIs, in vitro hepatic microsomal metabolism of GS-8374 was efficiently blocked by ritonavir, suggesting a potential for effective pharmacokinetic boosting in vivo. In summary, results from this broad in vitro pharmacological profiling indicate that GS-8374 is a promising candidate to be further assessed as a new antiretroviral agent with potential for clinical efficacy in both treatment-naive and -experienced patients.