New approaches to HIV protease inhibitor drug design II: testing the substrate envelope hypothesis to avoid drug resistance and discover robust inhibitors.
New approaches to HIV protease inhibitor drug design II: testing the substrate envelope hypothesis to avoid drug resistance and discover robust inhibitors.
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DOI：
10.1097/coh.0b013e3283136cee
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发表时间：
2008-11
影响因子：
4.1
通讯作者：
Schiffer CA
中科院分区：
文献类型：
--
作者：
Nalam MN;Schiffer CA
当抑制剂的结合和底物的周转之间的平衡被扰乱而有利于底物时，耐药性就会发生。对HIV-1蛋白酶抑制剂的耐药性相当广泛，允许蛋白酶处理其十种不同的底物。这种对底物的加工使HIV-1病毒成熟并具有感染性。设计与底物结合区紧密结合的HIV-1蛋白酶抑制剂是避免耐药性的一种策略。HIV-1蛋白酶与其底物的共晶体结构定义了重叠的底物结合区域或底物包膜。被设计成适合该底物包膜的新型HIV-1蛋白酶抑制剂被发现保留高结合亲和力，并且对一组耐药HIV-1蛋白酶具有平坦的结合特征。在最初设计抑制剂时需要考虑避免耐药性，以快速发展HIV-1蛋白酶等靶标。使用底物结合的详细知识似乎是实现这一目标的一个有前途的策略，以获得强大的HIV-1蛋白酶抑制剂。
Drug resistance occurs as a result when the balance between the binding of inhibitors and the turnover of substrates is perturbed in favor of the substrates. Resistance is quite wide spread to the HIV-1 protease inhibitors permitting the protease to process its ten different substrates. This processing of the substrates permits the HIV-1 virus to mature and become infectious. Designing HIV-1 protease inhibitors that closely fit within the substrate binding region is proposed to be a strategy to avoid drug resistance. Co-crystal structures of HIV-1 protease with its substrates define an overlapping substrate binding region, or substrate envelope. Novel HIV-1 protease inhibitors that were designed to fit within this substrate envelope, were found to retain high binding affinity and have a flat binding profile against a panel of drug resistant HIV-1 proteases. Avoiding drug resistance needs to be considered in the initial design of inhibitors to quickly evolving targets such as HIV-1 protease. Using a detailed knowledge of substrate binding appears to be a promising strategy for achieving this goal to obtain robust HIV-1 protease inhibitors.