Selective Plasmodium proteasome inhibitors as novel multi-stage antimalarials

选择性疟原虫蛋白酶体抑制剂作为新型多级抗疟药

基本信息

批准号：
10165483
负责人：
Gang Lin
金额：
$ 73.74万
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：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10165483
关键词：
Academia Active Sites Address Advanced Development Animal Model Antimalarials Asparagine Biochemical Bortezomib Caring Catalytic Domain Cessation of life Chemicals Chemistry Child Clinical Collaborations Collection Combined Modality Therapy Country Cryoelectron Microscopy Development Drug Kinetics Drug resistance Enzymatic Biochemistry Enzymes Erythrocytes Ethylenediamines Eukaryota Evaluation Foundations Genetic Transcription Goals Growth Human In Vitro Industry Institutes Lead Liver Malaria Mammalian Cell Mutation Oral Parasite resistance Parasites Parasitology Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phenotype Plasmodium Plasmodium falciparum Program Development Property Proteasome Inhibition Proteasome Inhibitor Protein Isoforms Proteins Regimen Regulation Reporting Resistance Resistance development Resolution Resources Risk Role Series Services Site Specificity Standardization Structure Testing Therapeutic Toxic effect Toxicology Ursidae Family Work base clinical development design experience global health high throughput screening improved in vitro activity in vivo inhibitor/antagonist lead optimization multicatalytic endopeptidase complex mutant mycobacterial novel organizational structure pre-clinical preservation prevent proteostasis resistance mechanism response scaffold synergism tool

项目摘要

Project Summary/Abstract Proteasome inhibitors kill Plasmodium spp. However, lack of malaria-specific proteasome inhibitors that spare human proteasomes has so far precluded treating malaria with drugs like bortezomib, carfilzomib and ixazomib, which have significant toxicity. There is an urgent need to develop malaria-specific proteasome inhibitors. Our past work, including substrate profiling, enzymology, structure-guided rational design and high throughput screening, led to discovery of the first species-selective proteasome inhibitors (active against mycobacterial proteasomes but not human proteasomes) as well as highly isoform-selective proteasome inhibitors (active against the human immunoproteasome but not the human constitutive proteasome). Informed by those experiences, we collaborated with Dr. Laura Kirkman, parasitologist and co-PI, to identify a novel class of compounds that kill P. falciparum in vitro but spare mammalian cells. These compounds inhibit the P. falciparum proteasome (Pf20S) ?5 subunit potently, noncovalently. The chemophore, subunit specificity, noncovalent reactivity and noncompetitive mode of inhibition of these compounds are distinctive compared to a Pf20S ?2 inhibitor recently reported by Bogyo's team, thereby offering an independent shot on goal against a well validated target, an opportunity to overcome resistance to one agent by using the other, and the possibility of synergistic results from using both, if they each lead to drugs. Our inhibitors are highly potent in inhibiting growth of P. falciparum at erythrocytic, liver, and gametocyte stages and are equally effective against P. falciparum isolates that are sensitive or resistant to current drugs. We have formed a novel organizational structure to pool the resources of the Lin chemistry/enzymology lab and the Kirkman parasitology lab (for which this support is requested) with the expertise of two major drug companies, each donating services through not-for-profit organizations (Tri-I Therapeutics Discovery Institute and its partner, Takeda Pharmaceuticals, and Tres Cantos Open Lab Foundation and its partner, GlaxoSmithKline). We now aim to continue our team approach to advance the development of malarial proteasome inhibitors as antimalarial drugs by improving their selectivity, specificity and pharmaceutical properties. Specific Aim 1 optimizes the hit compound series through rational design and concise and parallel synthesis, then determines their in vitro potency and selectivity, tests their anti-Plasmodium potency at erythrocytic, gametocytic, and liver stages, and improves their in vitro and in vivo pharmaceutical properties. Aim 2 investigates the mechanism of resistance to Pf20S inhibitors and the synergy of Pf20S inhibitors with other anti-malarial drugs.

项目概要/摘要蛋白酶体抑制剂可杀死疟原虫属。然而，缺乏疟疾特异性蛋白酶体抑制剂迄今为止，备用的人类蛋白酶体阻碍了用硼替佐米、卡非佐米等药物治疗疟疾和伊沙佐米（ixazomib），具有显着的毒性。迫切需要开发针对疟疾的药物蛋白酶体抑制剂。我们过去的工作，包括底物分析、酶学、结构引导合理的设计和高通量筛选，导致第一个物种选择性的发现蛋白酶体抑制剂（对分枝杆菌蛋白酶体有活性，但对人类蛋白酶体无效）作为高度异构体选择性蛋白酶体抑制剂（对人类免疫蛋白酶体有活性，但不人类组成型蛋白酶体）。根据这些经验，我们与劳拉博士合作寄生虫学家兼联合首席研究员柯克曼 (Kirkman) 鉴定出一类可在体外杀死恶性疟原虫的新型化合物但保留哺乳动物细胞。这些化合物抑制恶性疟原虫蛋白酶体 (Pf20S) ?5 亚基有效地，非共价地。趋化团、亚基特异性、非共价反应性和非竞争性与最近的 Pf20S ?2 抑制剂相比，这些化合物的抑制模式是独特的由 Bogyo 团队报告，从而针对经过充分验证的目标提供独立射门，通过使用另一种药物来克服对一种药物的耐药性的机会，以及协同作用的可能性如果两者都会产生毒品，那么两者都会产生结果。我们的抑制剂非常有效地抑制红细胞、肝脏和配子细胞阶段的恶性疟原虫对恶性疟原虫同样有效。对当前药物敏感或耐药的恶性疟原虫分离株。我们已经形成了一部小说汇集林化学/酶学实验室和柯克曼实验室资源的组织结构寄生虫学实验室（需要此支持）拥有两家主要制药公司的专业知识，每个通过非营利组织（Tri-I Therapeutics Discovery Institute 和其合作伙伴武田制药 (Takeda Pharmaceuticals) 和 Tres Cantos 开放实验室基金会及其合作伙伴，葛兰素史克）。我们现在的目标是继续我们的团队方法来推动疟疾的发展蛋白酶体抑制剂作为抗疟药物通过提高其选择性、特异性和药学特性。具体目标1通过合理的设计、简洁明了的方式，优化了热门化合物系列。平行合成，然后确定其体外效力和选择性，测试其抗疟原虫红细胞、配子细胞和肝脏阶段的效力，并改善它们的体外和体内药物特性。目标 2 研究 Pf20S 抑制剂的耐药机制和 Pf20S抑制剂与其他抗疟疾药物的协同作用。