In Vitro Antiviral Characteristics of HIV-1 Attachment Inhibitor BMS-626529, the Active Component of the Prodrug BMS-663068
In Vitro Antiviral Characteristics of HIV-1 Attachment Inhibitor BMS-626529, the Active Component of the Prodrug BMS-663068
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DOI：
10.1128/aac.00426-12
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发表时间：
2012-07-01
影响因子：
4.9
通讯作者：
Krystal, Mark
中科院分区：
文献类型：
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作者：
Nowicka-Sans, Beata;Gong, Yi-Fei;Krystal, Mark
BMS-663068是BMS-626529的phosphonooxymethyl前药，BMS-626529是一种新型的小分子附着抑制剂，靶向HIV-1 gp120并阻止其与CD4+ T细胞结合。由于gp120内的异质性，BMS-626529的活性依赖于病毒。为了更好地了解BMS-626529对HIV-1的抗谱，测定了其对多种实验室菌株和临床分离株的体外活性。BMS-626529对大多数易感病毒的半最大有效浓度（EC50）为6 log(10)，半最大有效浓度在低pM范围内。BMS-626529的体外抗病毒活性一般与嗜性或亚型无关，少数例外。测定BMS-626529对纯化gp120的结合亲和力表明，其抑制效力的一个因素可能是相对较长的解离半衰期。最后，在双药联合研究中，BMS-626529显示出与不同机制类别的抗逆转录病毒药物的加性或协同相互作用。这些结果表明BMS-626529应该对大多数HIV-1病毒有活性，并支持该化合物的持续临床开发。
BMS-663068 is the phosphonooxymethyl prodrug of BMS-626529, a novel small-molecule attachment inhibitor that targets HIV-1 gp120 and prevents its binding to CD4+ T cells. The activity of BMS-626529 is virus dependent, due to heterogeneity within gp120. In order to better understand the anti-HIV-1 spectrum of BMS-626529 against HIV-1, in vitro activities against a wide variety of laboratory strains and clinical isolates were determined. BMS-626529 had half-maximal effective concentration (EC50) values of 6 log(10), with half-maximal effective concentration values in the low pM range against the most susceptible viruses. The in vitro antiviral activity of BMS-626529 was generally not associated with either tropism or subtype, with few exceptions. Measurement of the binding affinity of BMS-626529 for purified gp120 suggests that a contributory factor to its inhibitory potency may be a relatively long dissociative half-life. Finally, in two-drug combination studies, BMS-626529 demonstrated additive or synergistic interactions with antiretroviral drugs of different mechanistic classes. These results suggest that BMS-626529 should be active against the majority of HIV-1 viruses and support the continued clinical development of the compound.