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

耐药性进化与药物设计的相互依赖性：HIV-1 蛋白酶

• 批准号: 8789525
• 负责人: Celia A. Schiffer
• 金额: $ 171.08万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8789525
• 关键词: Active Sites; Affinity; Binding; Biochemical; Biological Process; Case Study; Cell Culture Techniques; Characteristics; Complex; Computational Technique; Coupled; Data; Disease; Drug Design; Drug resistance; Drug resistance pathway; Engineering; Enzyme Kinetics; Enzymes; Equilibrium; Event; Evolution; Genome; HIV; HIV Protease Inhibitors; HIV-1; Health; Machine Learning; Methods; Minor; Molecular; Mutagenesis; Mutation; Pathway interactions; Patients; Pattern; Pattern Recognition; Peptide Hydrolases; Pharmaceutical Preparations; Physics; Plague; Point Mutation; Predisposition; Probability; Process; Protease Inhibitor; Quantitative Evaluations; Relative (related person); Resistance; Resistance development; Resistance profile; Scheme; Site; Societies; Structure; Technology; Testing; Therapeutic; Thermodynamics; Variant; Viral; Viral Proteins; Virus; analog; base; biological systems; data integration; deep sequencing; design; fitness; genome sequencing; improved; inhibitor/antagonist; molecular recognition; mouse model; novel; pressure; simulation; therapeutic target

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

描述：困扰我们社会的许多最致命的疾病发展迅速，挑战了我们大多数的治疗策略。进化的压力可能会导致抗性进化的各种途径。耐药可由分子识别事件平衡的改变引起，选择性地削弱抑制剂结合，但维持治疗靶点的生物学功能。为了减少耐药的可能性