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: 9904472
• 负责人: Nader Fotouhi
• 金额: $ 552.84万
• 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/9904472
• 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; 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; 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/antagonist; 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调节蛋白质的产生和降解