The Interdependency of Drug Resistance Evolution and Drug Design: HIV-1 Protease

描述：困扰我们社会的许多最致命的疾病演变得很快，对我们的大多数治疗策略提出了挑战。进化的压力可能会导致抗药性进化的多种途径。耐药可能是由于分子识别事件的平衡发生变化，选择性地削弱了抑制剂的结合，但保持了治疗靶点的生物学功能。为了减少抗药性的可能性， 必须阐明目标的功能在其存在的生物系统范围内的相互依存关系。干扰治疗靶点的活动是必要的，但不足以避免耐药性。在这项合作提案中，我们假设关键途径和耦合机制赋予治疗靶点耐药性。我们试图定义耐药相互依赖的序列、结构和动态以及时间上的进化限制：1)识别耐药发生的途径，2)设计药物设计策略，以开发出对耐药具有强大抵抗力的药物。HIV-1蛋白是一个完美的案例研究！艾滋病毒进化非常迅速，平均每复制三分之一的基因组就会引入一个点突变。HIV蛋白水解酶抑制剂有可能既非常有效，又对耐药性很强。蛋白酶抑制剂是唯一一类过渡态类似的HIV抑制剂，可以在进化过程中限制在底物包膜内。利用这两个特征的抑制剂，如达鲁那韦(DRV)和类似的类似物，有可能成为强大的、几乎耐药的抑制剂，用于未经药物治疗的艾滋病毒感染患者。如果艾滋病毒对这些抑制剂产生抗药性，那只能通过复杂的途径和突变的组合来实现。进一步阐明这些复杂的途径将使我们更接近耐药抑制剂。在这个项目中，我们的团队将使用和开发尖端技术来跟踪耐药选择的途径，阐明它们相互依赖的模式的分子基础，并将这些机制纳入药物设计策略。我们将共同努力解决抗药性问题，这是我们任何人都不可能单独实现的。

DESCRIPTION: Many of the most deadly diseases that plague our society evolve quickly, challenging most of our therapeutic strategies. The pressures of evolution will likely result in a variety of pathways for resistance to evolve. Drug resistance can be caused by a change in the balance of molecular recognition events that selectively weakens inhibitor binding but maintains the biological function of the therapeutic target. To reduce the likelihood of drug resistance, the interdependency of the target's function within the context of the biological system in which it exists must be elucidated. Disrupting the therapeutic target's activity is necessary but not sufficient for avoiding resistance. In this collaborative proposal we hypothesize that key pathways and coupled mechanisms confer drug resistance to therapeutic targets. We seek to define the sequence, structural and dynamic, and temporal evolutionary constraints of the interdependency of drug resistance: 1) to recognize the pathways by which resistance occurs and 2) to devise drug design strategies for developing a drug that is robust against resistance. HIV-1 Protease is the perfect case study! HIV evolves very quickly with on average a point mutation introduced in every third genome replicated. HIV protease inhibitors have the potential of being both very potent and robust to resistance. Protease inhibitors are the only HIV inhibitor class that are transition state analogs and can be evolutionarily constrained within the substrate envelope. Inhibitors that leverage both of these characteristics, such as Darunavir (DRV) and similar analogs, have the potential of being robust, nearly resistance proof inhibitors, to drug- na¿ve HIV infected patients. If HIV achieves resistance to these inhibitors it is only through complex pathways and combinations of mutations. Further elucidating these complex pathways will bring us closer to resistance-proof inhibitors. In this project our team will use and develop cutting-edge technology to follow the pathways of drug resistance selection, to elucidate the molecular basis for their interdependent patterns and incorporate these mechanisms into drug design strategies. Together we will make inroads into tackling drug resistance that would be impossible for any of us to individually achieve