New targets against tuberculosis

摘要 结核病是全球传染病死亡的主要原因，最近超过了 估计每年有140万人死于艾滋病。耐药结核病正在成为一个日益严重的 问题，包括最近出现的被指定为“完全抗药性”的菌株， 在应对这场危机的药物开发管道中，选择相对较少。耐药性的问题是 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 寻找对耐药结核分枝杆菌有效的新的治疗候选药物。 为了满足这一需要，我们建议开发一类新的化合物，4，6-二芳基取代 我们设计的通过一种新的作用机制来针对结核分枝杆菌的喹啉类药物。重要的是，我们有 证明了这一类具有良好的体内动物疗效，当每天给药一次和 口头上，在发现阶段只有很少的分子通过了障碍。事实上，领先候选人的ED50在 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病药物持平。 这些取代的喹啉类化合物通过抑制a的酶功能对结核分枝杆菌具有杀菌作用。 新的靶点FadD32，没有人类同源基因。重要的是，Fad32是 霉菌酸的生物合成，一种有效的治疗靶向途径，其突出作用说明 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。打击新靶点的新分子 在经过验证的路径中，具有双重优势，即基于已证实的 作用机制，同时克服对该途径的当前抑制剂的高水平耐药性。vt.给出 将动物的功效转化为人类的功效，抑制那些 被目前的结核病治疗成功地作为靶点的人增加了成功转化的可能性。 基础发现研究成功翻译的主要障碍之一是差距 在最初的基础研究发现和治疗开发之间。我们建议开发4，6-二芳基 领先的学术科学家和行业之间无缝、跨学科合作的Quonline 专业人士，他们以前都在一起工作过，他们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 通过结核病治疗的临床前开发，从Lead优化到IND备案。

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.