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 这个项目的总体目标是开发我们的新的稳定同位素标记的，版本的一个 现有的结核病（TB）药物异烟肼（INH）用于治疗耐药结核病。我们 假设我们同位素增强的化合物可以发展成一种强大的新的 针对INH耐药结核病和多药耐药结核病的药物，解决以下具体问题 目的： 具体目标1。确定其他INH耐药相关突变[酰基-13 C]INH可以 克服，并确定为什么[酰基-13 C]INH克服高INH的机制 突变体S315 T KatG菌株的抗性。 具体目标2。开发我们化合物的优化合成和技术转让 外部良好生产工艺的方案（TTP），符合GMP的生产。 具体目标3。收集非药物非临床研究质量管理规范（GLP）毒理学数据 化合物，以支持后续的GLP研究性新药（IND）使能研究。 顺利完成这些任务，将为风险投资资金和转移铺平道路 进行临床试验