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Novel mycobacterial translocase I inhibitors--a new class of anti-TB drugs

新型分枝杆菌易位酶I抑制剂——一类新型抗结核药物

基本信息

批准号：
7108305
负责人：
VENKATA M REDDY
金额：
$ 22.8万
依托单位：
SEQUELLA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-01 至 2008-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7108305
关键词：
culture enzymes lung model tuberculosis

项目摘要

DESCRIPTION (provided by applicant): Recent statistics lists tuberculosis (TB) as a serious infectious disease that kills nearly 2 million people worldwide each year. 1/3rd of the world's population is infected with the bacterial pathogen, M. tuberculosis (Mtb) that causes TB. HIV/AIDs increases the risk of getting TB and multi-drug resistant (MDR) Mtb strains are on the rise, threatening the world population. Treatment of TB requires multiple drugs delivered concurrently for at least 6 months. Failure to provide adequate drugs or to complete the long term therapy results in emergency of MDR Mtb. In order to control the current TB epidemic and finally eradicate the disease, new potent drugs that can shorten the treatment active disease and eliminate latently infected Mtb from asymptomatic patients are desperately needed. Since its founding in 1997, Sequella Inc. has been contributing its entire R&D efforts in the development of new tools for TB, including new drugs. Centered on the company's mission, this application describes the research plans for the development of a novel class of Mtb translocase I inhibitors that block the biosynthesis of peptidoglycan in the bacterial cell wall. The goal is to identify the best inhibitors in the class and to complete the pharmacological characterization of the compounds required for advancing 1 or more into preclinical phase of the development. 3 candidates (1 is a natural compound) initially discovered and studied at Sankyo Pharma Inc. inhibit Mtb growth in cultures and in infected mice, have low cytotoxicity, are active against MDR-Mtb, and show high tissue distribution in lungs. To continue the R&D of these compounds, we plan to evaluate their in vivo efficacy in mouse models of TB emphasizing on oral activity. We will explore pharmacophore diversity of the natural compound by chemical modification. The new derivatives will be filtered throughout a series of screens for ability to inhibit translocase I activity, inhibition of Mtb growth in culture (MIC determination), toxicity in human cells using MTS assay, and in vivo activity using a rapid mouse model of TB. The top hits selected from the original 3 and the new hits will be evaluated further for in vivo efficacy in a chronic mouse model of TB, in which the ability of each drug candidate to kill or inhibit Mtb replication in mouse lung and spleen of infected animals is determined directly by colony-forming units. This phase I proposal will allow us to select the most active anti-Mtb translocase I inhibitors that can be advanced to the next phase of drug development.

描述（由申请人提供）：最近的统计数据将结核病（TB）列为一种严重的传染病，每年在全世界造成近200万人死亡。世界上三分之一的人口感染了细菌病原体M。结核病（Mtb）是导致结核病的一种疾病。艾滋病毒/艾滋病增加了患结核病的风险，耐多药（MDR）结核病菌株正在增加，威胁着世界人口。结核病的治疗需要同时使用多种药物至少6个月。未能提供足够的药物或完成长期治疗导致MDR Mtb的紧急情况。为了控制目前的结核病流行并最终根除该疾病，迫切需要能够缩短治疗活动性疾病并从无症状患者中消除潜伏感染的Mtb的新的强效药物。自1997年成立以来，Sequella Inc.一直致力于研发结核病的新工具，包括新药。围绕该公司的使命，该申请描述了一种新型Mtb易位酶I抑制剂的开发研究计划，该抑制剂可阻断细菌细胞壁中肽聚糖的生物合成。目标是确定该类中最好的抑制剂，并完成将1种或多种药物推进到临床前开发阶段所需的化合物的药理学表征。3种候选化合物（1种为天然化合物）最初在Sankyo Pharma Inc.发现并研究。在培养物和感染小鼠中抑制Mtb生长，具有低细胞毒性，对MDR-Mtb有活性，并在肺中显示高组织分布。为了继续这些化合物的研发，我们计划评估它们在结核病小鼠模型中的体内功效，重点是口服活性。我们将通过化学修饰来探索天然化合物的药效团多样性。将通过一系列筛选来过滤新的衍生物，筛选其抑制易位酶I活性的能力、抑制培养物中Mtb生长的能力（MIC测定）、使用MTS测定的人细胞中的毒性以及使用快速TB小鼠模型的体内活性。将进一步评估从原始3个命中和新命中中选择的最高命中在TB的慢性小鼠模型中的体内功效，其中每种候选药物杀死或抑制感染动物的小鼠肺和脾中Mtb复制的能力直接由集落形成单位确定。这一I期提案将使我们能够选择最有效的抗结核杆菌移位酶I抑制剂，可以推进到药物开发的下一阶段。