Debyser Zeger, Cherepanov Peter, Van Maele Bénédicte, De Clercq Erik, Witvrouw Myriam
Rega Institute for Medical Research, KU Leuven, Flanders, Belgium.
Antivir Chem Chemother. 2002 Jan;13(1):1-15. doi: 10.1177/095632020201300101.
Current strategies for the treatment of HIV infection are based on cocktails of drugs that target the viral reverse transcriptase or protease enzymes. At present, the clinical benefit of this combination therapy for HIV-infected patients is considerable, although it is not clear how long this effect will last taking into account the emergence of multiple drug-resistant viral strains. Addition of new anti-HIV drugs targeting additional steps of the viral replication cycle may increase the potency of inhibition and prevent resistance development. During HIV replication, integration of the viral genome into the cellular chromosome is an essential step catalysed by the viral integrase. Although HIV integrase is an attractive target for antiviral therapy, so far all research efforts have led to the identification of only one series of compounds that selectively inhibit the integration step during HIV replication, namely the diketo acids. In this review we try to address the question why it has proven so difficult to find potent and selective integrase inhibitors. We point to potential pitfalls in defining an inhibitor as an authentic integrase inhibitor, and propose new strategies and technologies for the discovery of authentic HIV integration inhibitors.
目前治疗HIV感染的策略基于针对病毒逆转录酶或蛋白酶的药物组合。目前，这种联合疗法对HIV感染患者的临床益处相当大，尽管考虑到多种耐药病毒株的出现，尚不清楚这种效果能持续多久。添加针对病毒复制周期其他步骤的新型抗HIV药物可能会增强抑制效力并防止耐药性的产生。在HIV复制过程中，病毒基因组整合到细胞染色体中是由病毒整合酶催化的关键步骤。尽管HIV整合酶是抗病毒治疗的一个有吸引力的靶点，但迄今为止，所有的研究努力仅发现了一类能选择性抑制HIV复制过程中整合步骤的化合物，即二酮酸。在这篇综述中，我们试图探讨为何事实证明寻找强效且选择性的整合酶抑制剂如此困难。我们指出了将一种抑制剂定义为真正的整合酶抑制剂时可能存在的陷阱，并提出了发现真正的HIV整合抑制剂的新策略和新技术。
