Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 450 Brookline Avenue, CLS-1010, Boston, MA 02215, USA.
Curr Opin Chem Biol. 2013 Jun;17(3):339-45. doi: 10.1016/j.cbpa.2013.04.010. Epub 2013 May 3.
HIV-1 integrase is an important therapeutic target in the fight against HIV/AIDS. Integrase strand transfer inhibitors (INSTIs), which target the enzyme active site, have witnessed clinical success over the past 5 years, but the generation of drug resistance poses challenges to INSTI-based therapies moving forward. Integrase is a dynamic protein, and its ordered multimerization is critical to enzyme activity. The integrase tetramer, bound to viral DNA, interacts with host LEDGF/p75 protein to tether integration to active genes. Allosteric integrase inhibitors (ALLINIs) that compete with LEDGF/p75 for binding to integrase disrupt integrase assembly with viral DNA and allosterically inhibit enzyme function. ALLINIs display steep dose response curves and synergize with INSTIs ex vivo, highlighting this novel inhibitor class for clinical development.
HIV-1 整合酶是抗 HIV/AIDS 斗争中的一个重要治疗靶点。过去 5 年来，靶向酶活性位点的整合酶链转移抑制剂（INSTIs）已取得临床成功，但耐药性的产生对基于 INSTI 的治疗提出了挑战。整合酶是一种动态蛋白，其有序的多聚化对酶活性至关重要。与病毒 DNA 结合的整合酶四聚体与宿主 LEDGF/p75 蛋白相互作用，将整合固定在活性基因上。与 LEDGF/p75 竞争结合整合酶的变构整合酶抑制剂（ALLINIs）破坏整合酶与病毒 DNA 的组装，并变构抑制酶的功能。ALLINIs 显示陡峭的剂量反应曲线，并与 INSTIs 在体外协同作用，突出了这一新型抑制剂类别具有临床开发前景。
