Mechanism of Slow Onset Enzyme Inhibition and Translation to Time-Dependent Drug Activity

缓慢起效的酶抑制机制及其转化为时间依赖性药物活性

• 批准号: 10623704
• 负责人: PETER J TONGE
• 金额: $ 39.2万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623704
• 关键词: Acetyl-CoA Carboxylase; Amino Acyl-tRNA Synthetases; Animal Model; Anti-Bacterial Agents; Antibiotics; Cell model; Clinical Trials; Complex; Computational Biology; Coupled; Development; Drug Kinetics; Drug Modulation; Drug Targeting; Enzyme Inhibition; Enzyme Kinetics; Equilibrium; Event; Excision; Human; Human body; In Vitro; Infection; Kinetics; Link; Molecular; N-acetylglucosamine deacetylase; Pharmaceutical Preparations; Resources; Role; Safety; Structure; System; Therapeutic Agents; Time; Translations; drug action; drug candidate; drug discovery; drug efficacy; improved; in vivo; inhibitor; leucine-tRNA; mathematical model; novel strategies; novel therapeutics; residence; stem; structural biology; success

Many drug candidates fail in clinical trials due to lack of efficacy or insufficient safety. We speculate that our poor success rate at predicting in vivo drug efficacy stems from a reliance on in vitro assessments of drug activity that are performed at constant drug concentration (under equilibrium conditions), when in fact drug concentration is not constant in the human body. We thus propose that the kinetics of drug-target complex formation and breakdown is a critical factor in modulating drug action. In this proposal we will elucidate the molecular factors that dictate the impact of drug-target residence time on in vivo drug activity. These studies will focus on inhibitors of three antibacterial targets: UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC), acetyl-CoA carboxylase (ACC) and leucyl-tRNA synthetase (LeuRS). We will quantify the role that intracellular events such as target (re)synthesis, target degradation and target vulnerability have on the correlation between drug-target residence time and antibacterial activity determined as a function of drug concentration. This includes the prolongation of antibacterial activity following removal of drug from the system (the post-antibiotic effect). We will develop structure-kinetics relationships for time-dependent enzyme inhibition using a combination of structural and computational biology coupled with enzyme kinetics and synthesize inhibitors with extended target engagement. A mathematical model will be used that links drug-target kinetics and drug pharmacokinetics with predictions of antibacterial activity in whole cells and animal models of infection. Improved ability to predict in vivo drug action from in vitro parameters will have a dramatic impact on the discovery of new therapeutic agents.

许多候选药物因缺乏疗效或安全性不足而在临床试验中失败。我们 推测我们在预测体内药物功效方面的成功率很低源于对 在恒定药物浓度下进行的药物活性体外评估（在 平衡条件），而实际上药物浓度在人体内并不是恒定的。我们 因此提出药物-靶标复合物形成和分解的动力学是一个关键因素 调节药物作用。在这个提案中，我们将阐明决定的分子因素 药物靶标停留时间对体内药物活性的影响。这些研究将集中于抑制剂 三个抗菌靶点：UDP-3-O-(R-3-羟基肉豆蔻酰)-N-乙酰氨基葡萄糖脱乙酰酶 (LpxC)、乙酰辅酶A羧化酶(ACC)和亮氨酰-tRNA合成酶(LeuRS)。我们将量化 细胞内事件（例如靶标（再）合成、靶标降解和靶标）的作用 脆弱性对药物靶标停留时间和抗菌活性之间的相关性的影响 确定为药物浓度的函数。这包括延长抗菌作用 从系统中去除药物后的活性（抗生素后效应）。我们将开发 使用组合的时间依赖性酶抑制的结构动力学关系 结构和计算生物学与酶动力学相结合并合成抑制剂 延长目标参与度。将使用连接药物-靶标动力学的数学模型 和药物药代动力学，预测全细胞和动物的抗菌活性 感染模型。提高从体外参数预测体内药物作用的能力将 对新治疗药物的发现产生巨大影响。