Selective Plasmodium proteasome inhibitors as novel multi-stage antimalarials

项目概要/摘要 蛋白酶体抑制剂杀死疟原虫。然而，缺乏疟疾特异性蛋白酶体抑制剂， 到目前为止，多余的人类蛋白酶体已经排除了用硼替佐米、卡非佐米等药物治疗疟疾的可能性。 和Ixazomib，其具有显著的毒性。迫切需要制定针对疟疾的 蛋白酶体抑制剂。我们过去的工作，包括底物分析，酶学，结构导向 合理的设计和高通量筛选，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有效，但对人蛋白酶体无效） 作为高度同种型选择性蛋白酶体抑制剂（对人免疫蛋白酶体有活性，但不 人组成型蛋白酶体）。基于这些经验，我们与劳拉博士合作， Kirkman，寄生虫学家和合作PI，以确定一类新的化合物，杀死恶性疟原虫在体外 但保留了哺乳动物细胞这些化合物抑制恶性疟原虫蛋白酶体（Pf 20 S）？5亚基 有效地，非共价地。化学团，亚基特异性，非共价反应性和非竞争性 这些化合物的抑制模式是独特的相比，Pf 20 S？2抑制剂最近 Bogyo的团队报告，从而提供了一个独立的射门目标对一个良好的验证目标， 通过使用另一种药剂克服对一种药剂的耐药性的机会，以及协同增效的可能性。 如果两者都能导致吸毒，我们的抑制剂在抑制生长方面非常有效， P.在红细胞期、肝期和配子体期对恶性疟原虫具有同样的抗疟作用。 对现有药物敏感或耐药的恶性疟原虫分离株。我们写了一部小说 组织结构，以汇集林化学/酶学实验室和柯克曼的资源 寄生虫学实验室（为此请求提供支助），拥有两个主要制药公司的专门知识， 每个人都通过非营利组织（Tri-I Therapeutics Discovery Institute和 其合作伙伴武田制药和Tres Cantos开放实验室基金会及其合作伙伴， GlaxoSmithKline）。我们现在的目标是继续我们的团队方法，以促进疟疾的发展， 蛋白酶体抑制剂作为抗疟药的研究进展 特性.具体目标1通过合理的设计和简洁， 平行合成，然后测定它们的体外效力和选择性，测试它们的抗疟原虫活性， 在红细胞、配子体和肝脏阶段， 药物性质。目的2研究了水稻对Pf 20 S抑制剂的抗性机制， Pf 20 S抑制剂与其他抗疟疾药物的协同作用。

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.