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

基本信息

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
项目类别：
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

项目摘要

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）：诸如疟疾等传染病中抗药性的流行率需要努力识别新的抗感染剂。靶向必需的类异戊二烯生物合成酶是开发新抗疟药的潜在策略。该应用集中在化学策略的发明上，以允许针对晚期MEP途径酶，ISPG和Farnesylylophophathate合酶（FPPS）的两个极性抑制剂类别的细胞摄取和有效的细胞内激活。 FPP受到临床中使用的抗骨质疏松剂，唑来济元的有效抑制，而新出现的证据表明，酸苯二甲酸酯在体外施加抗寄生虫和抗菌作用。然而，这种双膦酸盐在生理pH中的聚苯二极管性质可防止在临床上可实现的血清浓度下有效地摄取对骨架外细胞的有效摄取。在实现高细胞内二磷酸类似物的高细胞内浓度时，旨在充当有效机制的MEP途径酶ISPG的抑制剂或其他MEP途径酶，其中类似的挑战将出现，或者是其他MEP途径酶，其中多磷酸化基团是抑制剂结合和识别的必不可少的组件。该应用提出了一种克服这些关键障碍的新型化学策略。拟议的研究将采用最小生物活化步骤开发前药激活化学，以揭示寄生虫内的多重负电荷。我们将实施这种策略，以显着增强靶向FPP靶向唑来膦酸盐（AIM 1）和靶向ISPG的线性双磷酸盐（AIM 2）的抗疟疾特性。这些研究将为高度极性，有效的类异on-生物合成抑制剂转化为有用的治疗剂，以治疗传染病。