Species selective dipeptide inhibitors for Mtb proteasome

Mtb 蛋白酶体的物种选择性二肽抑制剂

基本信息

批准号：
8607117
负责人：
Gang Lin
金额：
$ 21.13万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8607117
关键词：
ATP phosphohydrolase Abbreviations Anti-Infective Agents Antibiotics Bacteria Bioavailable Biochemical Biological Assay Biological Availability Cells Cessation of life Chemicals Client Collaborations Complement Complex Core Facility Crystallization Degradation Pathway Development Dipeptides Drug Kinetics Enzymes Genus Mycobacterium Goals Growth Hereditary Disease Heterogeneity Human In Vitro Inhibitory Concentration 50 Lead Libraries Ligase Mammals Metabolic Microsomes Modeling Mus Mycobacterium tuberculosis Nitric Oxide Outcome Oxygen Peptide Hydrolases Pharmaceutical Chemistry Pharmaceutical Preparations Play Population Predisposition Proteasome Inhibition Proteins Research Institute Resistance Rifampin Role Serum Starvation Sterilization Structure System Testing Therapeutic Translating Tuberculosis Ubiquitin Like Proteins bactericide base design feeding in vitro activity in vivo inhibitor/antagonist isoniazid killings multicatalytic endopeptidase complex mycobacterial nitrosative stress peptidomimetics protein degradation public health relevance public health research scale up screening stability testing structural biology tuberculosis drugs

项目摘要

DESCRIPTION (provided by applicant): In vitro activities do not always translate into in vivo activities, and this is true in Mycobacterium tuberculosis (Mtb) therapeutics. For example, the two first line anti-Mtb drugs isoniazid and rifampicin kill Mtb rapidly in vitro, but their steriliation abilities are slowed and reduced in vivo. Heterogeneity of Mtb populations imparts varied susceptibility to the drugs. In particular, slowly-replicating or non-replicating (collectively "NR) Mtb is non-heritably resistant to most first line anti-TB drugs. Our long-term goal is to develop anti-Mtb drugs that kill NR Mtb populations to complement drugs that kill replicating Mtb populations. During the past eight years, components of a prokaryotic ubiquitin-like protein (Pup)-proteasome system have been discovered. Although the Mtb proteasome is dispensable under standard growth conditions, genetic evidence demonstrates its essentiality for Mtb to survive in mice. We also established the concept that despite the essential role of the proteasome in mammals, small chemical molecules can be discovered with extensive (>1000-fold) species selectivity for inhibiting the Mtb proteasome over the human proteasome, and that such inhibition leads to killing of NR Mtb. In other bacteria, disruption of another regulated protein degradation machine, Clp, has led to killing. Thus, either inhibition or forced activation f chambered proteases may represent a new anti-infective strategy. In our recent screening of 1600 capped dipeptides, we identified a lead compound that potently and species-selectively inhibited the Mtb proteasome over the human proteasome. The inhibitors were bactericidal for non-replicating Mtb in synergy with nitric oxide. Using a competition assay, I confirmed that the dipeptides penetrate the mycobacteria and inhibit the proteasome within them. In this application, we will expand our lead compounds into a small focused compound library whose design and synthesis are guided by substrate-profiling, structural analysis, mycobactericidal activity, and metabolic stability.

描述（由申请人提供）：体外活动并不总是转化为体内活动，在结核分枝杆菌（MTB）疗法中确实如此。例如，两条第一线抗MTB药物异烟肼和利福平在体外迅速杀死MTB，但它们的灭菌能力在体内放缓并降低。 MTB种群的异质性赋予了对药物的各种敏感性。 In particular, slowly-replicating or non-replicating (collectively "NR) Mtb is non-heritably resistant to most first line anti-TB drugs. Our long-term goal is to develop anti-Mtb drugs that kill NR Mtb populations to complement drugs that kill replicating Mtb populations. During the past eight years, components of a prokaryotic ubiquitin-like protein (Pup)-proteasome system尽管在标准的生长条件下，MTB蛋白酶体是可分配的，但遗传证明了其在小鼠中生存的重要性，尽管蛋白酶体在哺乳动物中的重要作用，但小型化学分子可以通过抑制人类蛋白质的蛋白质来发现蛋白酶。 MTB。在其他细菌中，CLP的另一个受调节蛋白质降解机的破坏导致抑制作用或强制激活F室内蛋白酶可能代表一种新的抗感染策略。在最近对1600个上限二肽的筛查中，我们确定了一种铅化合物，该化合物有效地抑制了MTB蛋白酶体，而不是人类蛋白酶体。抑制剂是与一氧化氮协同作用的非重复MTB的杀菌剂。使用竞争测定法，我确认二肽穿透分枝杆菌并抑制其中的蛋白酶体。在此应用中，我们将将铅化合物扩展到一个小的聚焦化合物库中，该化合物的设计和合成是由底物 - 培训，结构分析，分生霉菌活性和代谢稳定性所指导的。