New targets against tuberculosis

防治结核病的新目标

基本信息

批准号：
10197774
负责人：
DEBORAH T HUNG
金额：
$ 107.68万
依托单位：
BROAD INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10197774
关键词：
Address Ames Assay Anabolism Animal Model Animals Antibiotics Automobile Driving Basic Science Binding Bioavailable Biochemical Biochemical Genetics Biochemistry Biological Biological Assay Biological Availability Biology Cause of Death Cells Chemicals Chronic Clinical Communicable Diseases Crystallization Data Development Discipline Disease Drug Interactions Drug resistance Drug resistance in tuberculosis Ensure Enzymes Fatty Acids Genetic study Goals HIV Health Homologous Gene Human In Vitro Industry Industry Standard Infection Investigational Drugs Ligase Light Maximum Tolerated Dose Measures Modeling Molecular Mechanisms of Action Mus Mutagenicity Tests Mycobacterium tuberculosis Mycolic Acid Oral Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Play Positioning Attribute Property Research Resistance Role Safety Scientist Series Solubility Structure Testing Therapeutic Therapeutic Agents Toxic effect Toxicogenomics Translating Translations Treatment Efficacy Tuberculosis Work acute infection analog animal efficacy axenic culture bactericide base biophysical analysis biophysical properties chronic infection clinical candidate clinical practice combat design drug development efficacy study first-in-human human study in vivo in vivo evaluation in vivo monitoring inhibitor/antagonist interdisciplinary collaboration isoniazid lead candidate lead optimization macrophage mouse model multiple drug use novel novel therapeutics pandemic disease pharmacokinetics and pharmacodynamics pre-clinical preclinical development preclinical safety quinoline receptor safety assessment safety study structural biology synergism therapeutic candidate therapeutic development therapeutic target tuberculosis drugs tuberculosis treatment

项目摘要

ABSTRACT Tuberculosis is the leading causes of death by infectious diseases worldwide, having recently surpassed HIV and killing an estimated 1.4 million people annually. Drug resistant tuberculosis is becoming an increasing problem, including the recent emergence of strains that have been designated “totally drug resistant,” with relatively few options in the drug development pipeline to combat this crisis. The problem of drug resistance is now posing a serious threat to the management of TB and human health. Increased efforts are urgently needed to identify new therapeutic candidates that are active against drug resistant Mycobacterium tuberculosis. To address this need, we propose to advance a novel chemical class of compounds, 4,6-diaryl substituted quinolines that we have designed to target M. tuberculosis by a new mechanism of action. Importantly, we have demonstrated that this class has excellent in vivo animal efficacy against TB when administered once-a-day and orally, a barrier passed by very few molecules at the discovery stage. In fact, the lead candidate has an ED50 in infected mice of 4.9 mg/kg, which makes it on par with some of the most potent current anti-tubercular drugs. These substituted quinolines are bactericidal against M. tuberculosis by inhibiting the enzymatic function of a new target, FadD32, for which there is no human homologue. Importantly, Fad32 is an essential enzyme in mycolic acid biosynthesis, a well-validated pathway for therapeutic targeting as illustrated by the prominent role played by another inhibitor of this pathway, isoniazid, in current TB therapy. New molecules that hit novel targets in validated pathways have the dual advantage of a high likelihood of therapeutic efficacy based on a proven mechanism of action while overcoming the high levels of resistance to current inhibitors of the pathway. Given that it has been extremely challenging to translate animal to human efficacy, inhibiting pathways or functions that have successfully been targeted by current TB therapy increases the likelihood of successful translation. One of the major hurdles to the successful translation of basic discovery research has been the gap between the initial basic research discovery and therapeutic development. We propose to develop the 4,6-diaryl quionlines in a seamless, interdisciplinary collaboration between leading academic scientists and industry professionals, all who have worked together previously, who will span the disciplines of TB biology, biochemistry, structural biology, medicinal chemistry, and pre-clinical PK/ADME/toxicity in order to progress this promising candidate through the preclinical development of TB therapeutics, from lead optimization to IND filing.

抽象的结核病是全世界传染病死亡的主要原因，最近已超过每年约有 140 万人死于艾滋病毒和耐药结核病。问题，包括最近出现的被指定为“完全耐药”的菌株，应对这场危机的药物开发途径相对较少耐药性问题是。现在对结核病的管理和人类健康构成严重威胁，迫切需要加大努力。以确定对耐药结核分枝杆菌具有活性的新候选治疗药物。为了满足这一需求，我们建议开发一类新型化合物，4,6-二芳基取代的我们设计的喹啉通过一种新的作用机制来靶向结核分枝杆菌。每天一次给药时，该类药物在动物体内具有出色的抗结核功效，并且口服，在发现阶段很少有分子能够通过这一屏障。事实上，主要候选药物的 ED50 为 0.55。感染小鼠的剂量为 4.9 毫克/公斤，这使其与目前一些最有效的抗结核药物相当。这些取代的喹啉通过抑制结核分枝杆菌的酶功能而具有杀菌作用。新靶点 FadD32，其没有人类同源物重要的是，Fad32 是一种必需酶。分枝菌酸生物合成，一种经过充分验证的治疗靶向途径，如其突出作用所示在当前的结核病治疗中，该途径的另一种抑制剂异烟肼发挥了作用，能够击中新靶标。经验证的途径具有双重优势，即基于已证实的治疗效果的可能性很高作用机制，同时克服对该途径现有抑制剂的高水平耐药性。将动物的功效转化为人类的功效、抑制途径或功能是极具挑战性的当前结核病治疗已成功靶向增加了成功转化的可能性。基础发现研究成功转化的主要障碍之一是差距我们建议开发 4,6-二芳基。 quionlines 在领先的学术科学家和工业界之间进行无缝的跨学科合作所有以前合作过的专业人士将跨越结核病生物学、生物化学、结构生物学、药物化学和临床前 PK/ADME/毒性，以推进这一前景广阔的研究结核病治疗药物的临床前开发（从先导化合物优化到 IND 申请）的候选者。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Discovery of heterocyclic replacements for the coumarin core of anti-tubercular FadD32 inhibitors.

DOI：
10.1016/j.bmcl.2018.09.037
发表时间：
2018-12-01
期刊：
Bioorganic & medicinal chemistry letters
影响因子：
2.7
作者：
Fang C;Lee KK;Nietupski R;Bates RH;Fernandez-Menendez R;Lopez-Roman EM;Guijarro-Lopez L;Yin Y;Peng Z;Gomez JE;Fisher S;Barros-Aguirre D;Hubbard BK;Serrano-Wu MH;Hung DT
通讯作者：
Hung DT