Membrane Permeable Diphosphate Analogs Targeting Pathogen Isoprenoid Biosynthesis

描述（由申请人提供）：疟疾等传染病的耐药性普遍存在，要求努力确定新的抗感染药物。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。该申请的重点是发明一种化学策略，允许细胞摄取和有效激活针对晚期MEP途径酶IspG和法尼基焦磷酸合成酶（FPPS）的两种极性抑制剂类。临床使用的抗骨质疏松药物唑来膦酸盐可以有效抑制FPPS，并且新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值下的多阴离子性质阻碍了临床可达到的血清浓度下有效的细胞摄取到骨骼外细胞。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，这些类似物被设计为MEP途径酶IspG或其他MEP途径酶的有效机制抑制剂，其中多磷酸化基团是抑制剂结合和识别的重要组成部分。该应用程序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物激活化学，采用最小的生物激活步骤来揭示寄生虫内的多个负电荷。我们将实施这一策略，以显著提高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、强效的类异戊二烯生物合成抑制剂转化为治疗传染病的有用治疗剂提供基础。

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.