Macrocyclic proteasome inhibitors for treatment of tuberculosis

用于治疗结核病的大环蛋白酶体抑制剂

基本信息

批准号：
9979179
负责人：
Gang Lin
金额：
$ 21.19万
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：
2020
资助国家：
美国
起止时间：
2020-03-09 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979179
关键词：
Abbreviations Antibiotics Attenuated Vaccines BCG Live Bacteria Bioavailable Biochemistry Biological Availability Biology Cell Wall Cells Cessation of life Chagas Disease Chemicals Chronic Phase of Disease Client Collaborations Colony-forming units Complement Complex Crystallization Degradation Pathway Development Drug Kinetics Drug Targeting Drug resistance Enzyme Inhibition Enzymes Excretory function Folic Acid Future Genetic Goals Growth HepG2 Human In Vitro Institutes Interferons Kinetics Knock-out Leishmaniasis Liver Microsomes Malaria Mass Spectrum Analysis Medicine Membrane Metabolic Metabolism Microbiology Multi-Drug Resistance Mus Mycobacterium bovis Mycobacterium smegmatis Mycobacterium tuberculosis NOS2A gene Nitric Oxide Nitrogen Nuclear Magnetic Resonance Nucleic Acids Nucleosome Core Particle Oral Outcome Pathway interactions Peptides Peripheral Blood Mononuclear Cell Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pharmacology Phenotype Physiological Play Population Proteasome Inhibitor Protein Biosynthesis Proteins Protozoa Rattus Regimen Research Institute Resources Role Safety Stress Structure Structure-Activity Relationship System Testing Therapeutic Toxic effect Trypsin Tuberculosis Ubiquitin Like Proteins United States National Institutes of Health Work absorption bactericide cytotoxicity design efficacy study enzyme activity extensive drug resistance hepatoma cell in vivo inhibitor/antagonist lead optimization mouse model multicatalytic endopeptidase complex mutant novel pathogen peptidomimetics protein degradation structural biology tuberculosis drugs tuberculosis treatment

项目摘要

Project Summary/Abstract Existing medicines for tuberculosis are losing ground to drug resistance. There is intense need to develop new regimens that include drugs active against Mycobacterium tuberculosis (Mtb) cells in the slowly- or non-replicating states (for simplicity, “NR” states) associated with phenotypic tolerance to most 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. Mtb relies on specific enzymatic pathways to survive the host stresses that make it NR. Among these is the prokaryotic ubiquitin-like protein (Pup)-proteasome system discovered over several years beginning in 2003. Although the Mtb proteasome is dispensable under standard growth conditions, it has been validated as a drug target both genetically and pharmacologically: the knock-out strain dies in the chronic phase of disease in mice, and we introduced several classes of Mtb proteasome inhibitors that kill NO-stressed or starved Mtb in vitro. These included the first inhibitors selective (>1000-fold) for the proteasome of a pathogen and not its host, and the first agents to kill bacteria by inhibiting protein breakdown rather than protein synthesis. Heretofore there have been only five broad classes of antibiotic targets: inhibition of synthesis of nucleic acids, proteins, cell walls and folate, and disruption of membranes. Our work has validated a fifth class: inhibition of a protein degradation pathway, and led to the discovery by others of pathogen-selective proteasome inhibitors that kill the protozoal agents of malaria, Chagas disease and Leishmaniasis. In this application, we will advance our newly discovered novel class of peptidomimetics. We demonstrate that these inhibitors are highly potent and species selective Mtb proteasome inhibitors. We propose to conduct lead optimization to achieve oral bioavailability with safety for future in vivo efficacy studies in mouse model of Mtb infection.

项目摘要/摘要现有的结核病药物正在失去耐药性。有很大的需求开发新的方案，包括针对结核分枝杆菌的药物（MTB）与慢速或非复制状态（为简单性，“ nr”状态）中的细胞与对大多数结核病药物的表型耐受性。我们的长期目标是开发杀死的抗MTB药物 NR MTB种群补充杀死复制MTB种群的药物。 MTB依靠特定的酶促途径可以在使其NR的宿主应力下生存。其中是多年来发现的原核泛素样蛋白（PUP） - 近调系统系统多年从2003年开始。虽然MTB蛋白酶体是可支配的理解标准增长条件，它已被一般和药物验证为药物靶标：在小鼠慢性疾病阶段的敲除菌株死亡，我们引入了几个在体外杀死无应激或饥饿的MTB的MTB蛋白酶体抑制剂类别。这些包括第一个抑制剂选择性（> 1000倍），用于病原体的蛋白酶体，而不是其宿主，以及第一个通过抑制蛋白质分解而不是蛋白质杀死细菌的药物合成。迄今核酸，蛋白质，细胞壁和叶酸的合成以及膜的破坏。我们的工作已经验证了第五类：抑制蛋白质降解途径，并导致了其他人发现杀死原生动物的病原体选择性蛋白酶体抑制剂疟疾，查加斯病和利什曼病。在此应用程序中，我们将推进新的发现了新颖的辣妹类。我们证明这些抑制剂很高潜在和物种选择性MTB蛋白酶体抑制剂。我们建议进行铅优化以实现口服生物利用度和安全性，以实现未来的体内效率研究 MTB感染的小鼠模型。