Membrane Permeable Diphosphate Analogs Targeting Pathogen Isoprenoid Biosynthesis

靶向病原体类异戊二烯生物合成的膜渗透性二磷酸类似物

• 批准号: 8416422
• 负责人: Caren L. Freel Meyers
• 金额: $ 20.25万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416422
• 关键词: Address; Amines; Anabolism; Anti-Bacterial Agents; Anti-Infective Agents; Antimalarials; Antiparasitic Agents; Attention; Binding; Cell Membrane Permeability; Cells; Charge; Chemicals; Chemistry; Communicable Diseases; Development; Dichloromethylene Diphosphonate; Diphosphates; Drug Targeting; Drug resistance; Elements; Enzymes; Evaluation; Exhibits; Foundations; Goals; Human; In Vitro; Iron; Malaria; Masks; Membrane; Methods; Mycobacterium tuberculosis; Nature; Nitrogen; Osteoporosis; Parasites; Parents; Pathway interactions; Permeability; Pharmaceutical Preparations; Physiological; Plasmodium falciparum; Prevalence; Prodrugs; Property; Research; Resistance development; Serum; Source; Staging; Sulfur; Testing; Therapeutic Agents; Translating; Work; Zoledronate; analog; base; bisphosphonate; design; enzyme pathway; farnesyl pyrophosphate; infectious disease treatment; inhibitor/antagonist; inorganic phosphate; interest; isoprenoid; novel; pathogen; physiologic model; prevent; public health relevance; scaffold; tool; uptake

DESCRIPTION (provided by applicant): The prevalence of drug-resistance in infectious diseases such as malaria demands efforts to identify new anti-infective agents. Targeting essential isoprenoid biosynthetic enzymes is a potential strategy for the development of new antimalarial agents. This application is focused on the invention of a chemical strategy to permit cellular uptake and efficient intracellular activation of two polar inhibitor classes targeting the late stage MEP pathway enzyme, IspG, and farnesylpyrophosphate synthase (FPPS). FPPS is potently inhibited by the clinically-used anti-osteoporosis agent, zoledronate, and emerging evidence suggests zoledronate exerts antiparasitic and antibacterial effects in vitro. However, the polyanionic nature of this bisphosphonate at physiologic pH prevents efficient cellular uptake into extraskeletal cells at clinically achievable serum concentrations. Similar challenges will exit in achieving high intracellular concentrations of linear diphosphate analogs designed to act as potent mechanism-based inhibitors of MEP pathway enzyme IspG, or other MEP pathway enzymes in which polyphosphorylated groups are essential components for inhibitor binding and recognition. This application proposes a novel chemical strategy to overcome these critical barriers. The proposed studies will develop prodrug activation chemistry employing minimal bioactivation steps to unmask multiple negative charges, within parasites. We will implement this strategy to dramatically enhance the antimalarial properties of FPPS-targeting zoledronate (Aim 1) and linear diphosphates targeting IspG (Aim 2). These studies will provide a foundation for the transformation of highly polar, potent inhibitors of isoprenoid biosynthesis into useful therapeutic agents for the treatment of infectious diseases.

描述（由申请人提供）：疟疾等传染病普遍存在耐药性，需要努力寻找新的抗感染药物。针对必需的类异戊二烯生物合成酶是开发新型抗疟药物的潜在策略。本申请的重点是发明一种化学策略，以允许细胞摄取和有效细胞内激活两种针对晚期 MEP 途径酶、IspG 和法呢基焦磷酸合酶 (FPPS) 的极性抑制剂。 FPPS 被临床使用的抗骨质疏松药物唑来膦酸盐有效抑制，新出现的证据表明唑来膦酸盐在体外具有抗寄生虫和抗菌作用。然而，这种双膦酸盐在生理 pH 值下的聚阴离子性质阻碍了细胞在临床可达到的血清浓度下有效摄取到骨外细胞中。在实现线性二磷酸类似物的细胞内高浓度方面也存在类似的挑战，这些类似物被设计作为MEP途径酶IspG或其他MEP途径酶的有效的基于机制的抑制剂，其中多磷酸化基团是抑制剂结合和识别的重要组成部分。该应用提出了一种新颖的化学策略来克服这些关键障碍。拟议的研究将开发前药活化化学，采用最少的生物活化步骤来揭示寄生虫内的多个负电荷。我们将实施这一策略，以显着增强靶向 FPPS 的唑来膦酸盐（目标 1）和靶向 IspG 的线性二磷酸盐（目标 2）的抗疟特性。这些研究将为将类异戊二烯生物合成的高极性、有效抑制剂转化为治疗传染病的有用治疗剂奠定基础。