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: 8281051
• 负责人: Caren L. Freel Meyers
• 金额: $ 24.3万
• 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 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8281051
• 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 Delivery Systems; 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）：疟疾等传染病的耐药性普遍存在，需要努力识别新的抗感染药物。靶向必需的类异戊二烯生物合成酶是开发新的抗疟药的潜在策略。本申请集中于化学策略的发明，以允许靶向晚期MEP途径酶IspG和法尼基焦磷酸合酶（FPPS）的两种极性抑制剂类别的细胞摄取和有效的细胞内活化。FPPS被临床使用的抗骨质疏松剂唑来膦酸盐有效抑制，新的证据表明唑来膦酸盐在体外发挥抗寄生虫和抗菌作用。然而，这种双膦酸盐在生理pH下的聚阴离子性质阻止了在临床上可达到的血清浓度下有效的细胞摄取到皮肤外细胞中。类似的挑战将存在于实现高细胞内浓度的线性二磷酸类似物中，所述线性二磷酸类似物被设计为充当MEP途径酶IspG或其中多磷酸化基团是抑制剂结合和识别的必要组分的其他MEP途径酶的有效的基于机制的抑制剂。本申请提出了一种新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，采用最小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，以显著增强FPPS靶向唑来膦酸盐（Aim 1）和线性二磷酸盐靶向IspG（Aim 2）的抗疟特性。这些研究将为将高极性、有效的类异戊二烯生物合成抑制剂转化为用于治疗感染性疾病的有用治疗剂提供基础。