Modulation of Protein production and Degradation as an integrated approach to rapid sterilization of Drug sensitive and resistant Mtb.

调节蛋白质产生和降解作为快速灭菌药物敏感和耐药结核分枝杆菌的综合方法。

• 批准号: 10388408
• 负责人: Nader Fotouhi
• 金额: $ 595.64万
• 依托单位: GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10388408
• 关键词: ATP phosphohydrolase; Advanced Development; Antitubercular Agents; Binding; Biochemical; Cell Death; Center for Translational Science Activities; Clinical; Clinical Trials; Collaborations; Complex; DNA-Directed RNA Polymerase; Data; Development; Disease; Dose; Drug Combinations; Drug Design; Drug Targeting; Drug resistance; Drug resistance in tuberculosis; Drug resistant Mycobacteria Tuberculosis; Enzymes; Extreme drug resistant tuberculosis; Fiber; Formulation; Genetic Transcription; Genetic study; Goals; In Vitro; Institution; Investigational Drugs; Investigational New Drug Application; Lead; Learning; Modeling; Multidrug-Resistant Tuberculosis; Mus; Mycobacterium tuberculosis; Natural Products; Oral; Oxazolidinones; Pathway interactions; Peptide Hydrolases; Peptides; Persons; Pharmaceutical Preparations; Process; Production; Protease Inhibitor; Protein Synthesis Inhibition; Proteins; RNA Polymerase Inhibitor; Regimen; Relapse; Research Project Grants; Resistance; Resistance development; Rifampin; Rifamycins; Site; Sterilization; Structure; System; Technology; Time; Translations; Treatment Protocols; Tuberculosis; base; candidate selection; chemical synthesis; computational chemistry; design; drug candidate; drug development; drug discovery; drug-sensitive; endopeptidase Clp; in vivo; inhibitor; lead optimization; mouse model; multidisciplinary; mutant; novel; pharmacokinetics and pharmacodynamics; pre-clinical; protein degradation; proteostasis; small molecule; therapy duration; tool; tuberculosis drugs; tuberculosis treatment

The main objective of the CETR is to modulate protein production and degradation as an integrated approach to rapid sterilization of drug sensitive (DS) and drug resistant tuberculosis (DR-TB) with the ultimate goal of delivering 2 investigational new drug (IND) applications and a regimen that will be effective against both DS and DR-TB and could result in relapse-free cures of TB-infected mice in 2 months or less, while also suppressing resistance development. Historically, TB treatment regimen development has been largely empiric. Our current treatment arises from serial clinical trials performed over the course of decades. Recently, we have accelerated this empiric process using a mouse model which, thus far, has excellent predictive power. However, any rationale for these regimens is ex post facto - we really do not understand why certain combinations are better than others. Here we will endeavor to devise a better regimen from first principles. We know that inhibition of RNA polymerase (RNAP) is clinically proven to shorten therapy dramatically and that rifampin synergizes with a variety of drugs. Using genetic studies, we have found that protein degradation is a particularly vulnerable process as even modest inhibition of Clp protease activity results in cell death. We reason that multiple insults in the “proteostasis” pathway that leads from transcription through translation and protein turnover will likely result in more potent TB treatment regimens. Indeed, our preliminary in vivo data suggest this is true. This multidisciplinary CETR consortium will bring together key expertise on three major drug targets that constitute the complex and coordinated network of processes that maintain proteostasis in TB. Through this highly interconnected set of projects and cores we will be able to: Identify modulators of the Clp protease complex by discovering an orally active modulator of ClpC1, and a small molecule ClpP1P2 protease inhibitor (Project 1 and Project 2 and Cores A, B and C). Using structure guided drug discovery approaches and the latest formulation technologies these modulators will be optimized and advanced to preclinical candidate selection. We expect at least one preclinical candidate to emerge from these various approaches. Identify novel RNAP inhibitors that bind and inhibit the enzyme at a non-overlapping site than rifamycins that will therefore be effective against both drug-sensitive and DR-TB (Project 3 and Cores A, B, and C). Use of structural information and computational chemistry will guide our effort to preclinical candidate selection. Using an in vitro hollow fiber system and mouse Mtb-infection models, we will characterize the PK/PD relationships that govern the anti-TB activity and suppression of drug-resistant mutants for each drug candidate (ClpC1 modulators [Project 1], ClpP1P2 modulators [Project 2], RNAP inhibitors [Project 3] and a safer oxazolidinone already identified and currently in IND enabling studies, [Project 4]) and deliver the optimal universally active regimen.

CETR 的主要目标是作为一种综合方法来调节蛋白质的产生和降解 快速灭菌药物敏感（DS）和耐药结核病（DR-TB），最终目标 提供 2 项研究性新药 (IND) 申请以及对两种 DS 均有效的治疗方案 和耐药结核病，并可能导致感染结核病的小鼠在两个月或更短的时间内无复发治愈，同时也 抑制耐药性的发展。从历史上看，结核病治疗方案的开发主要是 经验。我们目前的治疗源于数十年来进行的系列临床试验。最近， 我们使用小鼠模型加速了这一经验过程，迄今为止，该模型具有出色的预测能力。 然而，这些方案的任何理由都是事后的——我们真的不明白为什么某些 组合比其他组合更好。在这里，我们将努力从首要原则出发，设计出更好的治疗方案。我们 临床证明，抑制 RNA 聚合酶 (RNAP) 可以显着缩短治疗时间，并且 利福平与多种药物有协同作用。通过遗传学研究，我们发现蛋白质降解是 特别脆弱的过程，因为即使适度抑制 Clp 蛋白酶活性也会导致细胞死亡。我们 原因是从转录到翻译导致的“蛋白质稳态”途径中存在多种损伤 蛋白质周转可能会导致更有效的结核病治疗方案。事实上，我们的初步体内数据 表明这是真的。这个多学科的 CETR 联盟将汇集三个主要领域的关键专业知识 药物靶标构成维持蛋白质稳态的复杂且协调的过程网络 结核病。通过这组高度互连的项目和核心，我们将能够： Clp 蛋白酶复合物，发现 ClpC1 的口服活性调节剂和小分子 ClpP1P2 蛋白酶抑制剂（项目 1 和项目 2 以及核心 A、B 和 C）。使用结构引导药物发现 这些调节剂将通过方法和最新的配方技术进行优化和改进 临床前候选者选择。我们预计至少有一种临床前候选药物能够从这些不同的药物中脱颖而出。 接近。鉴定新型 RNAP 抑制剂，在非重叠位点结合并抑制该酶 因此，利福霉素可有效对抗药物敏感结核病和耐药结核病（项目 3 和核心 A、B、 和C）。结构信息和计算化学的使用将指导我们对临床前候选药物的努力 选择。使用体外中空纤维系统和小鼠 Mtb 感染模型，我们将表征 控制每种药物的抗结核活性和耐药突变体抑制的 PK/PD 关系 候选药物（ClpC1 调节剂 [项目 1]、ClpP1P2 调节剂 [项目 2]、RNAP 抑制剂 [项目 3] 和 已确定更安全的恶唑烷酮，目前正在进行 IND 启用研究，[项目 4]）并提供最佳 普遍积极的治疗方案。