Mazumder A, Neamati N, Sunder S, Schulz J, Pertz H, Eich E, Pommier Y
Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland 20892, USA.
J Med Chem. 1997 Sep 12;40(19):3057-63. doi: 10.1021/jm970190x.
We have previously reported the inhibitory activity of curcumin against human immunodeficiency virus type one (HIV-1) integrase. In the present study, we have synthesized and tested analogs of curcumin to explore the structure-activity relationships and mechanism of action of this family of compounds in more detail. We found that two curcumin analogs, dicaffeoylmethane (6) and rosmarinic acid (9), inhibited both activities of integrase with IC50 values below 10 microM. We have previously demonstrated that lysine 136 may play a role in viral DNA binding. We demonstrated equivalent potencies of two curcumin analogs against both this integrase mutant and wild-type integrase, suggesting that the curcumin-binding site and the substrate-binding site may not overlap. Combining one curcumin analog with the recently described integrase inhibitor NSC 158393 resulted in integrase inhibition which was synergistic, reflective of drug-binding sites which may not overlap. We have also determined that these analogs can inhibit binding of the enzyme to the viral DNA but that this inhibition is independent of divalent metal ion. Furthermore, kinetic studies of these analogs suggest that they bind to the enzyme at a slow rate. These studies can provide mechanistic and structural information which may guide the future design of integrase inhibitors.
我们之前报道了姜黄素对人类免疫缺陷病毒1型（HIV-1）整合酶的抑制活性。在本研究中，我们合成并测试了姜黄素类似物，以更详细地探索这类化合物的构效关系和作用机制。我们发现两种姜黄素类似物，二咖啡酰甲烷（6）和迷迭香酸（9），抑制整合酶的两种活性，IC50值低于10微摩尔。我们之前证明赖氨酸136可能在病毒DNA结合中起作用。我们证明这两种姜黄素类似物对这种整合酶突变体和野生型整合酶具有同等效力，表明姜黄素结合位点和底物结合位点可能不重叠。将一种姜黄素类似物与最近描述的整合酶抑制剂NSC 158393联合使用导致整合酶抑制具有协同作用，这反映了药物结合位点可能不重叠。我们还确定这些类似物可以抑制酶与病毒DNA的结合，但这种抑制与二价金属离子无关。此外，这些类似物的动力学研究表明它们以缓慢的速率与酶结合。这些研究可以提供可能指导未来整合酶抑制剂设计的机制和结构信息。
