Maurer K, Tang AH, Kenyon GL, Leavitt AD
Department of Laboratory Medicine
Bioorg Chem. 2000 Jun;28(3):140-155. doi: 10.1006/bioo.2000.1166.
Integration of a DNA copy of the HIV-1 genome is required for viral replication and pathogenicity, and this highly specific molecular process is mediated by the virus-encoded integrase protein. The requirement for integration, combined with the lack of a known analogous process in mammalian cells, makes integrase an attractive target for therapeutic inhibitors of HIV-1 replication. While many reports of HIV-1 IN inhibitors exist, no such compounds have yet emerged to treat HIV-1 infection. As such, new classes of integrase inhibitors are needed. We have combined molecular modeling and combinatorial chemistry to identify and develop a new class of HIV-1 integrase inhibitors, the Carbonyl J [N,N'-bis(2-(5-hydroxy-7-naphthalenesulfonic acid)urea] derivatives. This new class includes a number of compounds with sub-micromolar IC(50) values for inhibiting purified HIV-1 integrase in vitro. Herein we describe the chemical characteristics that are important for integrase inhibition and cell toxicity within the Carbonyl J derivatives. Copyright 2000 Academic Press.
HIV-1基因组的DNA拷贝整合是病毒复制和致病性所必需的，而这个高度特异性的分子过程由病毒编码的整合酶蛋白介导。整合的必要性，加上哺乳动物细胞中缺乏已知的类似过程，使得整合酶成为HIV-1复制治疗抑制剂的一个有吸引力的靶点。虽然有许多关于HIV-1整合酶抑制剂的报道，但尚未出现用于治疗HIV-1感染的此类化合物。因此，需要新型的整合酶抑制剂。我们结合分子建模和组合化学来鉴定和开发一类新型的HIV-1整合酶抑制剂，即羰基J [N，N'-双(2-(5-羟基-7-萘磺酸)脲]衍生物。这一新类包括许多在体外抑制纯化的HIV-1整合酶时IC(50)值为亚微摩尔级的化合物。在此我们描述了羰基J衍生物中对整合酶抑制和细胞毒性重要的化学特征。版权所有2000年，学术出版社。
