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

• 批准号: 10623176
• 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
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623176
• 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; Institution; Lead; Life Cycle Stages; 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; Work; 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

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。然而，缺乏疟疾特异的蛋白酶体抑制剂 到目前为止，多余的人类蛋白酶体排除了用波特佐米、卡菲佐米等药物治疗疟疾的可能性。 和ixazomib，这两种药物具有显著的毒性。迫切需要制定专门针对疟疾的 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的筛选，导致了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效，但对人类蛋白酶体无效) 作为高度异构体选择性的蛋白酶体抑制剂(对人类免疫蛋白酶体有效，但不是 人类构成的蛋白酶体)。受这些经历的启发，我们与劳拉博士合作 Kirkman，寄生虫学家和合作者Pi，在体外鉴定了一类新的杀死恶性疟原虫的化合物 而不是哺乳动物细胞。这些化合物抑制恶性疟原虫蛋白酶体(Pf20S)？5亚基。 强有力的，非共价性的。化学载体、亚基专一性、非共价反应性和非竞争性 与最近的Pf20S？2缓蚀剂相比，这些化合物的抑制模式是不同的 由Bogyo的团队报告，从而针对一个经过良好验证的目标提供了独立的射门， 通过使用一种药物来克服对另一种药物的耐药性的机会，以及协同作用的可能性 两者都使用的结果，如果它们都会导致毒品。我们的抑制剂具有很强的抑制肿瘤生长的作用。 恶性疟原虫在红细胞期、肝期和配子体阶段，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。我们组成了一部小说 汇集LIN化学/酶实验室和柯克曼实验室资源的组织结构 寄生虫学实验室(为此请求提供支持)，拥有两家主要制药公司的专业知识， 每个都通过非营利性组织(Tri-I治疗发现研究所和 它的合作伙伴武田制药和特雷斯·坎托斯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疾药物的选择性、特异性和药剂性 属性。具体目标1通过合理的设计和简洁的设计来优化Hit化合物系列 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 在红细胞、配子体和肝脏阶段的效力，并改善它们的体外和体内 药学特性。目的2探讨Pf20S抑制剂的耐药机制及耐药机制 Pf20S抑制剂与其他抗疟疾药物的协同作用。

项目成果

Protocol for analysis of intracellular conversion of artezomib molecules into new proteasome inhibitors in Plasmodium falciparum parasites.

恶性疟原虫寄生虫中阿替佐米分子细胞内转化为新型蛋白酶体抑制剂的分析方案。

• DOI: 10.1016/j.xpro.2024.102896
• 发表时间: 2024
• 期刊: STAR protocols
• 作者: Zhan,Wenhu;Liu,YiJing;Kirkman,LauraA;Lin,Gang
• 通讯作者: Lin,Gang

Microbial proteasomes as drug targets.

微生物蛋白酶体作为药物靶点。

• DOI: 10.1371/journal.ppat.1010058
• 发表时间: 2021-12
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Zhang H;Lin G
• 通讯作者: Lin G

Design, Synthesis, and Optimization of Macrocyclic Peptides as Species-Selective Antimalaria Proteasome Inhibitors.

• DOI: 10.1021/acs.jmedchem.2c00611
• 发表时间: 2022-07-14
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Zhang, Hao;Ginn, John;Zhan, Wenhu;Liu, Yi J.;Leung, Annie;Toita, Akinori;Okamoto, Rei;Wong, Tzu-Tshin;Imaeda, Toshihiro;Hara, Ryoma;Yukawa, Takafumi;Michino, Mayako;Vendome, Jeremie;Beuming, Thijs;Sato, Kenjiro;Aso, Kazuyoshi;Meinke, Peter T.;Nathan, Carl F.;Kirkman, Laura A.;Lin, Gang
• 通讯作者: Lin, Gang