Wu Bulan, Tang Jing, Wilson Daniel J, Huber Andrew D, Casey Mary C, Ji Juan, Kankanala Jayakanth, Xie Jiashu, Sarafianos Stefan G, Wang Zhengqiang
Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
Department of Molecular Microbiology and Immunology and Department of Biochemistry, Christopher S. Bond Life Sciences Center, University of Missouri , Columbia, Missouri 65211, United States.
J Med Chem. 2016 Jul 14;59(13):6136-48. doi: 10.1021/acs.jmedchem.6b00040. Epub 2016 Jun 17.
Resistance selection by human immunodeficiency virus (HIV) toward known drug regimens necessitates the discovery of structurally novel antivirals with a distinct resistance profile. On the basis of our previously reported 3-hydroxypyrimidine-2,4-dione (HPD) core, we have designed and synthesized a new integrase strand transfer (INST) inhibitor type featuring a 5-N-benzylcarboxamide moiety. Significantly, the 6-alkylamino variant of this new chemotype consistently conferred low nanomolar inhibitory activity against HIV-1. Extended antiviral testing against a few raltegravir-resistant HIV-1 clones revealed a resistance profile similar to that of the second generation INST inhibitor (INSTI) dolutegravir. Although biochemical testing and molecular modeling also strongly corroborate the inhibition of INST as the antiviral mechanism of action, selected antiviral analogues also potently inhibited reverse transcriptase (RT) associated RNase H, implying potential dual target inhibition. In vitro ADME assays demonstrated that this novel chemotype possesses largely favorable physicochemical properties suitable for further development.
人类免疫缺陷病毒（HIV）对已知药物方案产生耐药性，这就需要发现具有独特耐药谱的结构新颖的抗病毒药物。基于我们之前报道的3-羟基嘧啶-2,4-二酮（HPD）核心结构，我们设计并合成了一种新型整合酶链转移（INST）抑制剂，其具有5-N-苄基甲酰胺部分。值得注意的是，这种新化学类型的6-烷基氨基变体对HIV-1始终具有低纳摩尔抑制活性。对一些对拉替拉韦耐药的HIV-1克隆进行的扩展抗病毒测试显示，其耐药谱与第二代INST抑制剂度鲁特韦相似。尽管生化测试和分子建模也有力地证实了对整合酶的抑制是抗病毒作用机制，但所选的抗病毒类似物也能有效抑制逆转录酶（RT）相关的核糖核酸酶H，这意味着可能具有双重靶点抑制作用。体外药物代谢及药物动力学（ADME）分析表明，这种新型化学类型具有很大程度上有利的物理化学性质，适合进一步开发。
