Wlodawer A, Vondrasek J
Macromolecular Structure Laboratory, ABL-Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, Maryland 21702, USA.
Annu Rev Biophys Biomol Struct. 1998;27:249-84. doi: 10.1146/annurev.biophys.27.1.249.
Retroviral protease (PR) from the human immunodeficiency virus type 1 (HIV-1) was identified over a decade ago as a potential target for structure-based drug design. This effort was very successful. Four drugs are already approved, and others are undergoing clinical trials. The techniques utilized in this remarkable example of structure-assisted drug design included crystallography, NMR, computational studies, and advanced chemical synthesis. The development of these drugs is discussed in detail. Other approaches to designing HIV-1 PR inhibitors, based on the concepts of symmetry and on the replacement of a water molecule that had been found tetrahedrally coordinated between the enzyme and the inhibitors, are also discussed. The emergence of drug-induced mutations of HIV-1 PR leads to rapid loss of potency of the existing drugs and to the need to continue the development process. The structural basis of drug resistance and the ways of overcoming this phenomenon are mentioned.
十多年前，人们就已确定来自人类免疫缺陷病毒1型（HIV-1）的逆转录病毒蛋白酶（PR）是基于结构的药物设计的潜在靶点。这项工作非常成功。已有四种药物获批，其他药物正在进行临床试验。在这个结构辅助药物设计的显著例子中所使用的技术包括晶体学、核磁共振、计算研究和先进的化学合成。本文将详细讨论这些药物的研发情况。还将讨论基于对称性概念以及取代在酶和抑制剂之间呈四面体配位的水分子来设计HIV-1 PR抑制剂的其他方法。HIV-1 PR药物诱导突变的出现导致现有药物迅速失去效力，因此需要继续开展研发工作。文中提到了耐药性的结构基础以及克服这一现象的方法。
