Mycobacterial Proteasome Inhibitors

分枝杆菌蛋白酶体抑制剂

• 批准号: 8079914
• 负责人: CARL Francis NATHAN
• 金额: $ 49.96万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-21 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8079914
• 关键词: AIDS/HIV problem; Acidity; Acids; Affect; Amino Acids; Animals; Antibiotic Resistance; Antibiotics; Antitubercular Agents; Bacteria; Benzimidazoles; Benzofurans; Biological Preservation; Biology; Biomass; Bioterrorism; Blood; Bone Marrow; Boronic Acids; Bortezomib; Cells; Chemicals; Colony-forming units; Combination Drug Therapy; Development; Diabetes Mellitus; Disease; Docking; Dose; Drug Kinetics; Drug Resistant Tuberculosis; Drug resistance; Emergency Situation; Epidemic; Extreme drug resistant tuberculosis; Face; Frequencies; Genetic Transcription; Genus Mycobacterium; Growth; Human; Hypoxia; Imidazole; Immunodeficient Mouse; In Vitro; Indoles; Infection; Isoxazoles; Kinetics; Knock-out; Lead; Libraries; Lung; Mammalian Cell; Mass Spectrum Analysis; Maximum Tolerated Dose; Metabolic; Metabolic stress; Modeling; Multi-Drug Resistance; Mus; Mycobacterium tuberculosis; New Agents; Nitrites; Nitrogen; Nucleosome Core Particle; Obesity; Oxadiazoles; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenazines; Phenothiazines; Process; Proteasome Inhibitor; Proteins; Pteridines; Purines; Pyrazines; Pyrimidine; Pyrimidines; Pyrroles; Quinazolines; Recombinant Proteins; Recombinants; Research; Research Contracts; Resistance; Rifampin; Roentgen Rays; SKI gene; Scanning; Staging; Streptomycin; Structure; Substrate Specificity; Target Populations; Testing; Therapeutic; Therapeutic Index; Thiophenes; Translations; Triazines; Triazoles; Tuberculosis; Velcade; Work; antimicrobial drug; base; benzimidazole; benzothiophene; chemotherapy; combinatorial; design; global health; improved; inhibitor/antagonist; killings; latent infection; macrophage; man; meetings; member; monocyte; multicatalytic endopeptidase complex; mycobacterial; nitrosative stress; novel; pandemic disease; pathogen; peptidomimetics; pharmacophore; piperidine; protein complex; purine; pyridine; quinoline; reactive oxygen intermediate; response; theories; uptake

M. tuberculosis (Mtb) has caused a global health emergency that is rapidly worsening through the intersection of the tuberculosis (TB) pandemic with epidemics of antibiotic resistance, HIV/AIDS and obesity associated diabetes. Drug-resistant TB is a bioterrorism threat whose low potential to cause disease is offset by a high potential to disrupt the economy. Treatment of multi-drug resistant (MDR) and extensively drug resistant (XDR) TB is prolonged, costly and toxic and the fatality rate is high. Yet little new chemotherapy against Mtb has emerged in decades. An approach to chemotherapy introduced successfully by Dubos and Avery in 1931 but rarely tested since then is to target a pathway in the pathogen that is not essential for the pathogen to survive in vitro but is essential for the pathogen to resist conditions in the host. Mtb faces reactive nitrogen intermediates (RNI), reactive oxygen intermediates (ROI), acid, amino acid deficiency and other metabolic stresses when it infects the mouse and perhaps man, including during latent TB infection (LTBI). This application is based upon identification of the proteasome as a non-redundant pathway by which Mtb protects itself against oxidative/nitrosative stress and metabolic stringency. Although the proteasome is dispensable for growth of Mtb in rich media in vitro, it is essential for Mtb to survive in mice, even when the mice are immunodeficient. The Mtb proteasome is druggable both as a recombinant protein complex and within intact Mtb, and a clinically approved proteasome inhibitor, bortezomib (Velcade"), kills Mtb in vitro. Here we will explore and exploit the differences between proteasomes from Mtb and humans so as to develop inhibitors with sufficient species selectivity, mycobacterial uptake and nontoxicity to host cells to serve as leads for novel anti-TB chemotherapeutics. Our preliminary work suggests that members of two compound classes may meet these criteria: peptidyl boronates, the class that includes Velcade", and oxathiazol-2-ones, a class new to proteasome biology and medicinal chemistry. Lead compounds developed here could offer two new chemical classes for TB therapeutics, directed to a new target, effective against non-replicating Mtb and presumably active on Mtb resistant to existing drugs. Because they are effective against non-replicating Mtb and are likely to be orally active, oxathiazolones might be useful to treat LTBI in targeted populations to curtail the pandemic.

结核分枝杆菌（MTB）导致全球健康紧急情况，迅速恶化 通过结核病（TB）大流行与抗生素流行病的交集 抗药性，艾滋病毒/艾滋病与肥胖相关糖尿病。耐药结核病是 生物恐怖主义威胁其引起疾病潜力的低潜力被高潜力所抵消 破坏经济。多药耐药（MDR）和广泛药物的治疗 抗性（XDR）结核病的延长，昂贵和有毒，死亡率很高。但是很少 几十年来，针对MTB的新化疗已经出现。化学疗法的方法 Dubos和Avery在1931年成功引入了 靶向病原体中的一条途径，对于病原体生存而不是必需的途径 但对于抵抗宿主中的病原体是必不可少的。 MTB面部反应性 氮中间体（RNI），活性氧中间体（ROI），酸，氨基酸 当它感染老鼠甚至人时，缺乏症和其他代谢压力 包括在潜在结核病感染期间（LTBI）。此应用程序基于身份 蛋白酶体是一种非冗余途径，MTB可以保护自己免受 氧化/亚硝化应激和代谢严格性。虽然蛋白酶体是 在体外丰富培养基中MTB生长的可分配，MTB在 小鼠，即使小鼠免疫缺陷。 MTB蛋白酶体是可毒的 作为重组蛋白质复合物和完整的MTB，并经过临床批准 蛋白酶体抑制剂，硼替佐米（Velcade”），在体外杀死MTB。在这里我们将探索和 利用MTB和人类的蛋白酶体之间的差异，以发展 具有足够物种选择性，分枝杆菌摄取和无毒的抑制剂可宿主 细胞充当新型抗TB化学治疗剂的铅。我们的初步工作 建议两个化合物类的成员可能符合以下标准：肽基 富有卫星，包括Velcade的课程”和Oxathiazol-2-ones，这是一个新的班级 蛋白酶体的生物学和药物化学。这里开发的铅化合物可能 为结核病疗法提供两个新的化学班，针对新目标有效 反对非重复MTB，并可能活跃于对现有药物抗性的MTB。 因为它们有效防止非复制MTB，并且可能会口服活跃，所以 Oxathiazolones可能对靶向人群中的LTBI很有用，以减少 大流行。

项目成果

N,C-Capped dipeptides with selectivity for mycobacterial proteasome over human proteasomes: role of S3 and S1 binding pockets.

• DOI: 10.1021/ja400021x
• 发表时间: 2013-07-10
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Lin, Gang;Chidawanyika, Tamutenda;Tsu, Christopher;Warrier, Thulasi;Vaubourgeix, Julien;Blackburn, Christopher;Gigstad, Kenneth;Sintchak, Michael;Dick, Lawrence;Nathan, Carl
• 通讯作者: Nathan, Carl