LaFemina R L, Graham P L, LeGrow K, Hastings J C, Wolfe A, Young S D, Emini E A, Hazuda D J
Department of Antiviral Research, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Antimicrob Agents Chemother. 1995 Feb;39(2):320-4. doi: 10.1128/AAC.39.2.320.
The human immunodeficiency virus type 1 (HIV-1) integrase protein is required for the productive infection of T-lymphoid cells in culture (R. L. LaFemina, C. L. Schneider, H. L. Robbins, P. L. Callahan, K. LeGrow, E. Roth, W. A. Schleif, and E. A. Emini, J. Virol. 66:7414-7419, 1992). This observation suggests that chemical inhibitors of integrase may prevent the spread of HIV in infected individuals. In our search for such potential chemotherapeutic agents, we observed that beta-conidendrol inhibits both the sequence-dependent and sequence-independent endonucleolytic activities of integrase with comparable potencies in vitro (50% inhibitory concentration, 500 nM). Structurally related compounds tested for their abilities to inhibit integrase generated a limited structure-activity analysis which demonstrated that potency is associated with the bis-catechol structure: two pairs of adjacent hydroxyls on separate benzene rings. beta-Conidendrol did not inhibit several other endonucleases and/or phosphoryltransferases. Although beta-conidendrol was not effective in preventing HIV-1 infection in cell culture, the in vitro data demonstrate that it is possible to identify selective agents targeted against this essential HIV-1 function.
1型人类免疫缺陷病毒（HIV-1）整合酶蛋白是培养的T淋巴细胞进行有效感染所必需的（R. L. 拉费米纳、C. L. 施奈德、H. L. 罗宾斯、P. L. 卡拉汉、K. 勒格罗、E. 罗斯、W. A. 施莱夫和E. A. 埃米尼，《病毒学杂志》66:7414 - 7419，1992年）。这一观察结果表明，整合酶的化学抑制剂可能会阻止HIV在受感染个体中的传播。在我们寻找此类潜在化疗药物的过程中，我们发现β-松柏苷元在体外对整合酶的序列依赖性和序列非依赖性内切核酸酶活性具有同等效力的抑制作用（50%抑制浓度，500 nM）。对测试其抑制整合酶能力的结构相关化合物进行的有限构效分析表明，效力与双儿茶酚结构有关：在不同苯环上的两对相邻羟基。β-松柏苷元不抑制其他几种内切核酸酶和/或磷酸转移酶。虽然β-松柏苷元在细胞培养中不能有效预防HIV-1感染，但体外数据表明，有可能鉴定出针对这种HIV-1必需功能的选择性药物。
