Reversing Isoniazid Resistance By Isotopic Substitution

通过同位素替代逆转异烟肼耐药性

• 批准号: 9347156
• 负责人: GRAHAM S TIMMINS
• 金额: $ 58.64万
• 依托单位: SPINCEUTICA, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-06 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9347156
• 关键词: Address; Adverse effects; Affect; Blinded; Breath Tests; Capital Financing; Cell Nucleus; Chemistry; Complement; Contracts; Coupling; Data; Deuterium; Development; Drug Kinetics; Drug effect disorder; Drug resistance; Drug resistance in tuberculosis; Free Radicals; Funding; Future; Goals; Human; Hydrogen; Investigational Drugs; Isoniazid resistance; Isotopes; Kinetics; Knowledge; Label; Laboratories; Legal patent; Literature; Magnetism; Medicine; Metabolism; Multidrug-Resistant Tuberculosis; Mutation; Mycobacterium tuberculosis; Pathway interactions; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Positioning Attribute; Privatization; Process; Protocols documentation; Public Health; Reaction; Resistance; Rifampin; Risk; Running; Science; Scientist; Silk; Site; Small Business Innovation Research Grant; Stable Isotope Labeling; System; Technology Transfer; Testing; Toxic effect; Toxicology; Treatment Cost; Tuberculosis; Work; active control; drug discovery; good laboratory practice; improved; in vivo; isoniazid; magnetic field; manufacturing process; mutant; novel; novel strategies; novel therapeutics; pre-clinical; research clinical testing; resistance mechanism; resistant strain; scale up; stable isotope; theories; tuberculosis drugs

Project Summary The overall goal of this project is to develop our new stable isotope labeled, version of an existing tuberculosis (TB) drug, isoniazid (INH) for use in treated drug resistant TB. We hypothesize that our that isotope-enhanced compound can be developed into a powerful new drug against INH-resistant TB and multidrug resistant-TB, by addressing the following specific aims: Specific Aim 1. Determine what other INH resistance-associated mutations [acyl-13C]INH can overcome, and determine the mechanism for why [acyl-13C]INH overcomes the high INH resistance of mutant S315T KatG strains. Specific Aim 2. Develop an optimized synthesis of our compound and a Technology Transfer Protocol (TTP) for external good manufacturing processes, GMP-capable manufacture. Specific Aim 3. Collect non-Good Laboratory Practices (GLP) toxicology data on our compound to support subsequent GLP Investigational New Drug (IND) enabling studies. Successful completion of these tasks will pave the way for venture capital funding and transfer of our compound into clinical testing.

项目摘要 该项目的总体目标是开发我们的新稳定同位素标记，版本 现有的结核病（TB）药物，用于治疗耐药性结核病的异烟肼（INH）。我们 假设我们的同位素增强化合物可以发展成为一个有力的新型 通过解决以下特定的特异性，对INH耐药结核和多药耐药-TB进行毒品 目标： 具体目标1。确定其他与INH抗性相关的突变[Acyl-13c] inh可以 克服，并确定为什么[酰基-13c] INH克服高INH的机制 突变体S315T KATG菌株的抗性。 特定目的2。开发我们化合物和技术转移的优化合成 外部良好制造过程的协议（TTP），具有GMP功能的制造。 特定目的3。收集非良好实验室实践（GLP）毒理学数据 支持随后的GLP研究新药（IND）促成研究的化合物。 这些任务的成功完成将为风险资本资金和转移铺平道路 我们的化合物进入临床测试。