Plasmodium Protein Kinase Focused Antimalarials Discovery

疟原虫蛋白激酶聚焦抗疟药的发现

• 批准号: 10663334
• 负责人: DEBOPAM CHAKRABARTI
• 金额: $ 76.9万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-11 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663334
• 关键词: Address; Affect; Africa; Aminopyridines; Animal Model; Anti-Infective Agents; Antimalarials; Appearance; Artemisinins; Binding Sites; Biochemical; Biological; Biological Assay; Biology; Blood; California; Cellular biology; Cessation of life; Chemicals; Child; Collaborations; Collection; Combined Modality Therapy; Copy Number Polymorphism; Cyclic AMP-Dependent Protein Kinases; Development; Dose; Drug Industry; Drug resistance; Erythrocytes; Evaluation; Evolution; Exhibits; FDA approved; Falciparum Malaria; Florida; Goals; Hydrophobicity; In Vitro; Infection; Interdisciplinary Study; Knowledge; Laboratories; Lead; Lipids; Liver; Malaria; Methods; Modeling; Molecular; Molecular Conformation; Molecular Target; Multi-Drug Resistance; Mus; Oncogenic; Parasite resistance; Parasites; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phenotype; Phosphorylation; Phosphotransferases; Plasmodium; Plasmodium falciparum; Plasmodium falciparum genome; Plasmodium vivax; Population; Predisposition; Property; Prophylactic treatment; Protein Kinase; Proteins; Relapse; Reporting; Research; Resistance; Resistance profile; Resources; Route; Signal Pathway; Source; Southeastern Asia; Testing; Therapeutic; Thiophenes; Universities; Validation; analog; asexual; cancer therapy; design; drug development; efficacy evaluation; genome sequencing; global health; human disease; humanized mouse; improved; in vivo; inhibitor; inhibitor therapy; kinase inhibitor; knock-down; mouse model; nanomolar; next generation; novel; optimism; pharmacologic; pharmacophore; phosphoproteomics; prophylactic; protein kinase inhibitor; pyridine; resistant strain; scaffold; screening; small molecule therapeutics; targeted treatment; whole genome

Malaria still afflicts about half of the world population causing more than 400,000 deaths, mostly children. It is quite alarming that the options for malaria therapy are increasingly becoming limited because of widespread drug resistance. Furthermore, most of the antimalarials act only on the erythrocytic stages, the drugs for prophylaxis and relapse of malaria are suboptimal. To address the fragility of malaria therapy, we propose to discover and optimize next generation antimalarials acting on underexplored Plasmodium kinases. We will leverage wealth of knowledge on diverse chemical scaffolds and know-how related to the drug development and tolerability of kinase inhibitor-based therapies for various human diseases. We will focus on type II kinase inhibitors that have been designed to overcome selectivity issues by using both the ATP-binding site as well as the adjacent hydrophobic region created by the activation loop in the inactive conformation. To the best of our knowledge, type II inhibitors are yet to be explored as antimalarial agents. Premise for this proposal is based on our promising preliminary screening that has identified type II compounds with therapeutic and prophylactic activities. The goal of this project is to test the hypothesis that we can design effective type II chemical scaffolds that act on multiple stages of parasite development. To achieve this goal, we propose to pursue the following: (1) Design and synthesize optimized selective antimalarial type II compounds for in vivo application; antiplasmodial hits will be optimized to improve potency, selectivity, and pharmacological properties through stages of iterative analog design, synthesis, and evaluation of biological and biochemical activities. (2) Determine rate of killing, resistance profile, stage susceptibility, and efficacy of lead compounds in murine and humanized mouse models. Furthermore, the ability of the lead compounds to inhibit liver stage infection and gametocyte maturation will be assessed. 3) We will identify targets of antimalarial chemotypes using in vitro evolution of resistance followed by whole genome sequencing. We will use conditional knockdown and copy number variation of the resistance determinants for target validation. We will conduct phosphoproteomics analysis to uncover signaling pathways modulated by the type II inhibitors under study. The research in this endeavor will be conducted through a multidisciplinary collaboration between the laboratories of Debopam Chakrabarti (University of Central Florida), Nathanael Gray (Stanford University), Elizabeth Winzeler (University of California San Diego) with combined expertise in medicinal chemistry, kinase chemical biology, malaria cell biology, anti-infective discovery, target identification, and validation. Successful completion of these goal will lead to the discovery of novel chemical leads with therapeutic and prophylactic potential.

疟疾仍然困扰着世界约一半人口，导致超过 40 万人死亡，其中大部分是儿童。这是 令人震惊的是，由于疟疾广泛传播，治疗疟疾的选择越来越有限。 耐药性。此外，大多数抗疟药仅作用于红细胞阶段， 疟疾的预防和复发并不理想。为了解决疟疾治疗的脆弱性，我们建议 发现并优化作用于尚未开发的疟原虫激酶的下一代抗疟药。我们将 利用各种化学支架的丰富知识以及与药物开发相关的专业知识 以及基于激酶抑制剂的疗法对各种人类疾病的耐受性。我们将重点关注 II 型激酶 旨在通过使用 ATP 结合位点和 由非活性构象中的激活环产生的相邻疏水区域。尽我们最大的努力 据了解，II 型抑制剂作为抗疟药物仍有待探索。本提案的前提是基于 我们的初步筛选很有前景，已鉴定出具有治疗和预防作用的 II 型化合物 活动。该项目的目标是检验我们可以设计有效的 II 型化学品的假设 作用于寄生虫发育的多个阶段的支架。为了实现这一目标，我们建议追求 以下：（1）设计和合成优化的选择性抗疟II型化合物用于体内应用； 抗疟原虫命中将被优化，以通过以下方式提高效力、选择性和药理学特性： 生物和生化活性的迭代模拟设计、合成和评估阶段。 (2) 确定先导化合物在小鼠和小鼠体内的杀灭率、耐药性、阶段易感性和功效 人源化小鼠模型。此外，先导化合物抑制肝期感染的能力和 将评估配子细胞的成熟度。 3) 我们将利用体外鉴定抗疟化学型的靶标 耐药性的进化，随后进行全基因组测序。我们将使用条件击倒和复制 用于目标验证的抗性决定因素的数量变化。我们将进行磷酸蛋白质组学 分析以揭示所研究的 II 型抑制剂调节的信号通路。这方面的研究 这一努力将通过 Debopam 实验室之间的多学科合作来进行 Chakrabarti（中佛罗里达大学）、Nathanael Gray（斯坦福大学）、Elizabeth Winzeler （加州大学圣地亚哥分校）拥有药物化学、激酶化学生物学方面的综合专业知识， 疟疾细胞生物学、抗感染发现、靶标识别和验证。顺利完成 这些目标将导致发现具有治疗和预防潜力的新型化学先导化合物。

项目成果

Discovery of Potent Antimalarial Type II Kinase Inhibitors with Selectivity over Human Kinases.

发现比人类激酶具有选择性的强效抗疟 II 型激酶抑制剂。

• DOI: 10.1021/acs.jmedchem.3c02046
• 发表时间: 2024-01-12
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Lushun Wang;Monica J Bohmer;Jinhua Wang;Flore Nardella;Jaeson Calla;Mariana Laureano de Souza;Kyra A. Schindler;Lukas Montejo;Nimisha Mittal;Frances Rocamora;Mayl;Treat;Jordan T Charlton;Patrick K. Tumwebaze;Philip J Rosenthal;Rol;A Cooper;Ratna Chakrabarti;E. Winzeler;Debopam Chakrabarti;N. Gray
• 通讯作者: N. Gray