Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, United States.
J Med Chem. 2011 Apr 14;54(7):2282-92. doi: 10.1021/jm1014378. Epub 2011 Mar 7.
Integrase (IN) represents a clinically validated target for the development of antivirals against human immunodeficiency virus (HIV). Inhibitors with a novel structure core are essential for combating resistance associated with known IN inhibitors (INIs). We have previously disclosed a novel dual inhibitor scaffold of HIV IN and reverse transcriptase (RT). Here we report the complete structure-activity relationship (SAR), molecular modeling, and resistance profile of this inhibitor type on IN inhibition. These studies support an antiviral mechanism of dual inhibition against both IN and RT and validate 3-hydroxypyrimidine-2,4-diones as an IN inhibitor scaffold.
整合酶 (IN) 是临床验证的抗人类免疫缺陷病毒 (HIV) 抗病毒药物开发的靶标。具有新型结构核心的抑制剂对于对抗与已知整合酶抑制剂 (INIs) 相关的耐药性至关重要。我们之前已经披露了 HIV IN 和逆转录酶 (RT) 的新型双重抑制剂支架。在这里，我们报告了这种抑制剂类型对 IN 抑制的完整结构-活性关系 (SAR)、分子建模和耐药性特征。这些研究支持了针对 IN 和 RT 的双重抑制的抗病毒机制，并验证了 3-羟基嘧啶-2,4-二酮作为 IN 抑制剂支架。
