Macrocyclic proteasome inhibitors for treatment of tuberculosis

用于治疗结核病的大环蛋白酶体抑制剂

• 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
• 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

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.

项目总结/摘要 现有的结核病药物正在因耐药性而失去优势。有强烈的需求 开发新的治疗方案，包括抗结核分枝杆菌（Mtb）的药物 处于缓慢或非复制状态（为简单起见，“NR”状态）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抗结核药物， NR Mtb种群以补充杀死复制的Mtb种群的药物。MTB依赖于 特定的酶途径，以生存的主机应力，使其NR。其中， 近几年发现的原核泛素样蛋白（Pup）-蛋白酶体系统 从2003年开始。虽然结核分枝杆菌蛋白酶体在标准生长条件下生长缓慢， 条件下，它已被验证为药物靶点遗传和代谢： 敲除菌株在小鼠疾病的慢性期死亡，我们引入了几个 在体外杀死NO应激或饥饿的Mtb的Mtb蛋白酶体抑制剂的类别。这些 包括对病原体的蛋白酶体选择性（>1000倍）的第一抑制剂，而不是其 宿主，并且是第一种通过抑制蛋白质分解而不是蛋白质来杀死细菌的药剂 合成.迄今为止，只有五大类抗生素靶点： 核酸、蛋白质、细胞壁和叶酸的合成，以及膜的破坏。我们 工作已经验证了第五类：抑制蛋白质降解途径，并导致了 其他人发现了病原体选择性蛋白酶体抑制剂，可杀死原生动物病原体 疟疾、南美锥虫病和利什曼病。在这个应用程序中，我们将推进我们的新 发现了一类新的肽模拟物。我们证明，这些抑制剂是高度 有效和物种选择性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，并安全用于未来的体内疗效研究， Mtb感染的小鼠模型。