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

许多困扰我们社会的最致命的疾病迅速演变，挑战我们的大多数治疗策略。进化的压力很可能会导致抗性进化的各种途径。耐药性可由分子识别事件的平衡变化引起，其选择性地减弱抑制剂结合但维持治疗靶标的生物学功能。为了减少耐药性的可能性， 必须阐明目标在其存在的生物系统中的功能的相互依赖性。破坏治疗靶点的活性是必要的，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耐药性的治疗目标。我们试图定义顺序，结构和动态，以及时间进化的相互依赖性的耐药性的限制：1）认识耐药性发生的途径和2）设计药物设计策略，开发一种药物，是强大的抵抗耐药性。HIV-1蛋白酶是完美的案例研究！艾滋病毒进化非常迅速，平均每三个复制的基因组中就有一个点突变。HIV蛋白酶抑制剂具有非常有效和耐药性强的潜力。蛋白酶抑制剂是唯一的HIV抑制剂类别，是过渡态类似物，可以在进化上限制在底物包膜内。利用这两种特征的抑制剂，如达芦那韦（DRV）和类似物，对于未经药物治疗的HIV感染患者来说，有可能成为稳健的、几乎耐药的抑制剂。如果艾滋病毒对这些抑制剂产生耐药性，那只能通过复杂的途径和突变的组合。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，阐明其相互依赖模式的分子基础，并将这些机制纳入药物设计策略。我们将共同努力，在解决耐药性问题上取得进展，这是我们任何一个人单独都不可能实现的

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- naïve 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