Plasmodium Protein Kinase Focused Antimalarials Discovery

疟原虫蛋白激酶聚焦抗疟药的发现

• 批准号: 10533634
• 负责人: DEBOPAM CHAKRABARTI
• 金额: $ 80.13万
• 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/10533634
• 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; Pharmacology; 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; Testing; Therapeutic; Thiophenes; Universities; Validation; analog; asexual; base; 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; 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.

疟疾仍然折磨着大约一半的世界人口，造成40万多人死亡，主要是儿童。这是 令人震惊的是，由于普遍存在，疟疾疗法的选择变得越来越有限 耐药性。此外，大多数抗疟疾作用仅在红细胞阶段，这些药物 预防和疟疾的复发是最佳的。为了解决疟疾疗法的脆弱性，我们建议 发现并优化作用于未充满疟原虫激酶的下一代抗疟药。我们将 利用各种化学脚手架的知识和与药物开发有关的知识 激酶抑制剂对各种人类疾病的疗法的耐受性。我们将专注于II型激酶 旨在通过使用ATP结合站点以及旨在克服选择性问题的抑制剂 非活性构象中的激活环产生的相邻疏水区。尽我们所能 知识，II型抑制剂尚待探讨为抗疟药。该提案的前提是基于 在我们有希望的初步筛选中，该筛选已鉴定出具有治疗和预防性的II型化合物 活动。该项目的目的是测试我们可以设计有效II型化学的假设 在寄生虫发展的多个阶段起作用的脚手架。为了实现这一目标，我们建议追求 如下：（1）设计和合成用于体内应用的优化选择性的II型II型化合物； 将优化抗原流命中率，以提高效力，选择性和药理特性 迭代模拟设计，合成和生物化学活动的评估阶段。 （2） 确定杀戮的速率，抗性特征，阶段敏感性和铅化合物在鼠和 人源化的小鼠模型。此外，铅化合物抑制肝阶段感染的能力和 将评估配子细胞的成熟。 3）我们将使用体外确定抗疟疾化学型的靶标 阻力的演变，然后是整个基因组测序。我们将使用有条件的敲低并复制 目标验证的电阻决定因素的数字变化。我们将进行磷酸蛋白质组学 分析以发现研究的II型抑制剂调节的信号通路。这项研究 努力将通过Debopam实验室之间的多学科合作进行 Chakrabarti（佛罗里达州中部大学），纳塔纳尔·格雷（斯坦福大学），伊丽莎白·温泽勒 （加利福尼亚大学圣地亚哥分校）具有药物化学专业知识，激酶化学生物学， 疟疾细胞生物学，抗感染发现，靶标识别和验证。成功完成 这些目标将导致发现具有治疗和预防潜力的新型化学铅。