Validation of the ubiquinone synthesis pathway of Toxoplasma gondii as a novel drug target

弓形虫泛醌合成途径作为新药物靶点的验证

• 批准号: 10608408
• 负责人: Silvia N Moreno
• 金额: $ 41.57万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608408
• 关键词: Acquired Immunodeficiency Syndrome; Allergic Reaction; Anabolism; Antiparasitic Agents; Bone Diseases; Cells; Chemicals; Chemotherapy-Oncologic Procedure; Chronic; Clinic; Clinical; Congenital Toxoplasmosis; Country; Cryptosporidiosis; Cyst; Data; Diphosphates; Disease; Drug Kinetics; Drug Targeting; Drug usage; Electron Transport; Electron Transport Complex III; Electrons; Enzymes; Fetus; Future; Genetic; Geranyltranstransferase; Growth; HIV; Head; Human; Immunocompetent; Immunocompromised Host; Immunosuppression; In Vitro; Infection; Isomerism; Laboratories; Lead; Malaria; Mammalian Cell; Membrane; Mitochondria; Modeling; Morbidity - disease rate; Mus; Neuraxis; Organ Transplantation; Outcome; Parasites; Pathogenesis; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Phenotype; Plants; Population; Pregnancy; Property; Quinolones; Quinones; Research; Resistance; Supplementation; Tail; Techniques; Testing; Tissues; Toxoplasma gondii; Toxoplasmosis; Treatment Failure; Ubiquinone; Validation; Water; Work; Yeasts; acute infection; atovaquone; bisphosphonate; chemotherapy; chronic infection; cytotoxicity; effective therapy; experience; farnesyl pyrophosphate; fosmidomycin; gene complementation; geranylgeranyl diphosphate; hydroxybenzoate; hypercholesterolemia; improved; inhibitor; inorganic phosphate; isopentenyl pyrophosphate; isoprenoid; knock-down; lipophilicity; member; mevalonate; mortality; mouse model; new therapeutic target; novel; opportunistic pathogen; shikimate; small molecule libraries; tool; ubiquinone 6

PROJECT SUMMARY/ABSTRACT Apicomplexan parasites cause persistent mortality and morbidity worldwide through diseases including malaria, toxoplasmosis, and cryptosporidiosis. The phylum member Toxoplasma gondii alone infects approximately one third of the world population. T. gondii is an opportunistic pathogen that causes serious disease in immunocompromised patients. Most human infections are asymptomatic but immunosuppression due to organ transplant, cancer chemotherapy, or infection with HIV can lead to re-activation of the infection. In addition, infection of the fetus during pregnancy causes congenital toxoplasmosis. Some exotic strains of T. gondii have been described in tropical countries that cause severe ocular disease in immunocompetent patients. Treatment for toxoplasmosis is challenged by lack of effective drugs to eradicate the chronic infection and as many as one-third of AIDS patients do not respond to the therapy. Most of the drugs currently used are poorly distributed to the central nervous system and they trigger allergic reactions in a large number of patients. There is a compelling need for safe and effective treatments for toxoplasmosis. The mitochondrion of T. gondii and of other apicomplexan parasites is critical for replication and several major antiparasitic drugs, such as atovaquone and endochin-like quinolones, act through inhibition of the mitochondrial electron transport chain at the coenzyme Q:cytochrome c reductase. The coenzyme Q (UQ) molecule consists of a water soluble quinone head (para-hydroxybenzoate or PHBA) that can accept or donate two electrons and a lipophilic isoprenoid tail that confines the UQ to membranes. Synthesis of the PHBA moiety in plants and yeast occurs through the shikimate pathway, but how it is synthesized in apicomplexan is not known. The isoprenoid unit derives from a common precursor, isopentenyl pyrophosphate (IPP), and its isomer, dimethylallyl pyrophosphate (DMAPP), which are synthesized in mammalian cells via the mevalonate pathway, but in T. gondii instead is synthesized via an apicoplast localized methylerythritol phosphate (MEP) pathway. IPP and DMAPP are condensed by the action of a unique farnesyl diphosphate synthase (TgFPPS) into farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP). Work from our laboratory demonstrated that T. gondii is able to salvage GGPP and FPP from the host and therefore intracellular parasites are vulnerable to inhibition of the host isoprenoid synthesis pathway. In this project we propose to investigate the synthesis of UQ (downstream to the salvage point) and validate the pathway as a novel target. Our preliminary data demonstrates the essentiality of three enzymatic steps and the inhibition of one of them by a novel compound. Our hypothesis is that the synthesis of UQ represents a unique and essential pathway with enzymatic steps liable to inhibition by specific compounds, some already in use in the clinics and potential new ones to be discovered. We predict that exploring this pathway will reveal unique and essential enzymes that could be targeted for improved chemotherapy against T. gondii and other apicomplexan parasites.

项目摘要/摘要 Apicomplexan寄生虫通过包括 疟疾，弓形虫病和隐孢子虫病。单独的门弓形虫弓形虫单独感染 大约三分之一的世界人口。 T. gondii是一种机会性病原体，导致严重 免疫功能低下的患者的疾病。大多数人类感染是无症状但免疫抑制 由于器官移植，癌症化疗或HIV感染可导致感染重新激活。 此外，怀孕期间的胎儿感染会导致先天性毒质剂。 T。一些异国情调的菌株。 在热带国家中描述了贡迪，这些国家在免疫能力的 患者。缺乏有效的药物来消除慢性感染的挑战，造成毒性肿瘤的治疗挑战 多达三分之一的艾滋病患者对该疗法没有反应。当前使用的大多数药物是 分布不佳到中枢神经系统，并引发大量患者的过敏反应。 对弓形虫病的安全有效疗法的需求迫切有必要。 T. gondii和其他Apicomplexan寄生虫的线粒体对于复制至关重要，有几个 主要的抗寄生虫药物，例如atovaquone和类似内胆素的奎诺酮，通过抑制作用 辅酶的线粒体电子传输链Q：细胞色素C还原酶。辅酶Q（UQ） 分子由可以接受或捐赠的水溶性奎因酮头（Para-Hydroxybenzoate或PHBA）组成 两个电子和一个限制UQ与膜的亲脂性异丙也是尾巴。 PHBA部分的合成 在植物和酵母中，通过Shikimate途径发生，但是如何在Apicomplexan中合成它 已知。异普尼单元源自共同的前体，等苯基焦磷酸（IPP），其 异构体，二甲基二磷酸（DMAPP），它们通过甲谷酸盐在哺乳动物细胞中合成 途径，但在gondii中，通过蛋白酶局部甲基疫醇磷酸盐（MEP）合成。 路径。 IPP和DMAPP由独特的Farnesyl二磷酸合酶（TGFPPS）的作用凝结 进入Farnesyl二磷酸（FPP）和黄烷基二磷酸（GGPP）。从我们的实验室工作 证明T. gondii能够从宿主那里挽救GGPP和FPP，因此细胞内 寄生虫很容易受到抑制宿主类异戊二烯合成途径。在这个项目中，我们建议 研究UQ的合成（下游到打捞点），并将途径验证为新的靶标。 我们的初步数据证明了三个酶促步骤的重要性，并且抑制了其中一个 通过一种新颖的化合物。我们的假设是，UQ的合成代表了独特而必不可少的途径 酶促的步骤可通过特定化合物抑制，其中一些已经在诊所使用和潜力 新的要发现。我们预测，探索这一途径将揭示独特而必不可少的酶 这可以针对改善针对T. gondii和其他Apicomplexan寄生虫的化学疗法。