Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
ACS Chem Biol. 2013 Mar 15;8(3):513-8. doi: 10.1021/cb3006193. Epub 2012 Dec 27.
Understanding the interdependence of multiple mutations in conferring drug resistance is crucial to the development of novel and robust inhibitors. As HIV-1 protease continues to adapt and evade inhibitors while still maintaining the ability to specifically recognize and efficiently cleave its substrates, the problem of drug resistance has become more complicated. Under the selective pressure of therapy, correlated mutations accumulate throughout the enzyme to compromise inhibitor binding, but characterizing their energetic interdependency is not straightforward. A particular drug resistant variant (L10I/G48V/I54V/V82A) displays extreme entropy-enthalpy compensation relative to wild-type enzyme but a similar variant (L10I/G48V/I54A/V82A) does not. Individual mutations of sites in the flaps (residues 48 and 54) of the enzyme reveal that the thermodynamic effects are not additive. Rather, the thermodynamic profile of the variants is interdependent on the cooperative effects exerted by a particular combination of mutations simultaneously present.
理解多种突变在赋予药物抗性方面的相互依存关系对于开发新型和强大的抑制剂至关重要。随着 HIV-1 蛋白酶不断适应和逃避抑制剂，同时仍然保持特异性识别和有效切割其底物的能力，药物抗性问题变得更加复杂。在治疗的选择压力下，相关突变在整个酶中积累，从而损害抑制剂的结合，但描述它们的能量相互依存关系并不简单。一个特定的耐药变体（L10I/G48V/I54V/V82A）相对于野生型酶表现出极端的熵焓补偿，但类似的变体（L10I/G48V/I54A/V82A）则没有。酶的瓣（残基 48 和 54）中的位点的单个突变表明，热力学效应不是加性的。相反，变体的热力学特征取决于同时存在的特定突变组合所产生的协同效应的相互依赖性。
