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：
10404078
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/10404078
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 lead optimization multicatalytic endopeptidase complex mutant mycobacterial novel organizational structure pre-clinical preservation prevent proteostasis rational design 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.

项目摘要/摘要蛋白酶体抑制剂杀死疟原虫。但是，缺乏疟疾特异性蛋白酶体抑制剂到目前为止，备用人类蛋白酶体排除了用硼替佐米，carfilzomib等药物治疗疟疾和ixazomib，具有明显的毒性。迫切需要开发特定于疟疾的蛋白酶体抑制剂。我们过去的工作，包括底物分析，酶学，结构引导理性的设计和高吞吐量筛选，导致发现了第一个物种选择性蛋白酶体抑制剂（对分枝杆菌蛋白酶体的活性，而不是人类蛋白酶体）作为高度同工型选择性蛋白酶体抑制剂（对人免疫蛋白酶体的活性，但不活跃人类本构蛋白酶体）。通过这些经验，我们与劳拉博士合作柯克曼（Kirkman），寄生虫学家兼Co-Pi，以确定一类新型的化合物，这些化合物在体外杀死恶性疟原虫但是备用哺乳动物细胞。这些化合物抑制恶性疟原虫蛋白酶体（PF20S）？5亚基有力，非共价。化学成分，亚基特异性，非共价反应性和非竞争性与PF20S相比，这些化合物的抑制方式是独特的？由Bogyo的团队报告，从而为实现良好的目标提供了独立投篮，通过使用另一个来克服对一个代理的抵抗的机会，并有协同作用的可能性使用两者都会导致毒品。我们的抑制剂在抑制生长方面非常有效恶性疟原虫在红细胞，肝脏和配子细胞阶段，对P.同样有效。对当前药物敏感或抗性的恶性分离株。我们已经形成了一本小说组织结构来汇集Lin Chemistry/酶学实验室和Kirkman的资源寄生虫实验室（要求提供此支持），并具有两家主要制药公司的专业知识，通过非营利组织（Tri-I Therapeutics Discovery Institute和它的合作伙伴Takeda Pharmaceuticals和Tres Cantos Open Lab Foundation及其合作伙伴，葛兰素史克林）。现在，我们的目标是继续我们的团队方法来促进疟疾的发展蛋白酶体抑制剂作为抗疟药，通过提高其选择性，特异性和药物特性。特定目标1通过理性设计和简洁，优化热门化合物系列，然后平行合成，然后确定其体外效力和选择性，测试其抗质量红细胞，配子细胞和肝脏阶段的效力，并改善其体外和体内药物特性。 AIM 2研究了对PF20抑制剂的抗性机制和 PF20S抑制剂与其他抗疟疾药物的协同作用。