Development of the potent anti-malarial and anti-Toxoplasma drug, ELQ-316

开发强效抗疟疾和抗弓形虫药物 ELQ-316

• 批准号: 8810588
• 负责人: Joseph Stone Doggett
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8810588
• 关键词: Active Sites; Acute; Affect; Amino Acids; Antimalarials; Atovaquone resistance; Award; Babesia microti; Binding; Biochemical; Biological Availability; Biological Models; Caring; Catalysis; Chemicals; Communicable Diseases; Computer Simulation; Computers; Cytochrome bc1 Complex; Development; Drug Combinations; Drug Design; Drug Exposure; Drug Kinetics; Drug resistance; Drug usage; Electron Transport; Encephalitis; Enzymes; Eye diseases; Funding; Future; Health; Health Sciences; In Vitro; Infection; Kinetics; Lead; Leishmania; Libraries; Malaria; Measures; Medical center; Medicine; Mentors; Methods; Military Personnel; Mitochondria; Modeling; Molecular; Molecular Models; Mus; Mutagenesis; Mutation; Oral; Oregon; Parasite resistance; Parasitology; Pharmaceutical Preparations; Physicians; Plasmodium; Plasmodium falciparum; Point Mutation; Preclinical Drug Development; Preclinical Testing; Prodrugs; Protozoa; Publications; Publishing; Qi; Quinolones; Research; Research Personnel; Resistance; Resistance development; Respiratory Chain; Saccharomyces cerevisiae; Science; Senior Scientist; Series; Services; Site; Solubility; Staging; Testing; Time; Toxicology; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Training; Trypanosoma; Universities; Veterans; Wood material; aqueous; atovaquone; base; career; career development; design; drug development; drug discovery; drug mechanism; drug testing; enzyme activity; experience; improved; in vivo; inhibitor/antagonist; interest; iterative design; meetings; molecular modeling; mortality; mutant; neglected tropical diseases; novel; pathogen; preclinical evaluation; public health relevance; research clinical testing; research study; respiratory; symposium

Malaria is one of the leading causes of mortality in the world. Current therapy for malaria is limited by drug resistance. Toxoplasma gondii is found worldwide and causes devastating eye disease and encephalitis. Current therapy for toxoplasmosis is poorly tolerated and does not eradicate infection from its host. Veterans are exposed to these infections during their military service and new treatments would greatly improve veterans' health. Dr. Doggett and his colleagues have developed new drugs, endochin like quinolones (ELQ), that are highly effective against malaria and T. gondii. He has chosen ELQ-316 as a lead drug because it is orally available, non-toxic and highly effective. Dr. Doggett's preliminary studies in T. gondii and Saccharomyces cerevisiae suggest that ELQs inhibit the mitochondrial cytochrome bc1 complex (cyt bc1). Dr. Doggett will test the hypothesis that ELQ-316 inhibits cyt bc1 and characterize how ELQ-316 interacts with the cyt bc1. He will also test if inhibiting both active sites of cyt bc1 reduces P. falciparum's ability to develop drug resistance. Dr. Doggett will test this hypothesis by measuring the rate of resistance against the combination of ELQ-316 with atovaquone and the rate of resistance of ELQ-316 against a P. falciparum clone that has atovaquone resistance. If mutations occur in both cyt bc1 active sites, he will measure the catalytic activity of the enzyme. Dr. Doggett will optimize the administration of ELQ-316 by finding synergistic combinations of ELQ-316 with clinically used drugs against toxoplasmosis and malaria, determining the pharmacokinetics of ELQ-316 orally and transdermally, and developing an ELQ-316 prodrug. Dr. Doggett is an infectious disease physician at Oregon Health & Sciences University and the Portland VA Medical Center. He is specifically interested in new treatments for neglected tropical diseases that effect veterans. He has carried out research in Dr. Mike Riscoe's lab investigating drug mechanism of action and drug resistance in protozoan pathogens. Dr. Doggett has developed proficiency in the biochemical and molecular methods that are needed for his current research plan. The VA CDA-2 award will provide Dr. Doggett further training in drug mechanism and new training in pharmacokinetics, drug design and computer based molecular modeling. As a part of a robust training plan, Dr. Doggett has selected a panel of senior scientists with expertise in molecular parasitology, T. gondii, Plasmodia, preclinical drug development and S. cerevesiae as a model system. This panel is experienced in mentoring early investigators and will meet with Dr. Doggett formally every 6 months. The panel will provide advice regarding experiments, publications and career development. In addition, Dr. Doggett will attend the Woods Hole molecular parasitology course, attend science courses at OHSU and present his research at conferences. This award will culminate in the establishment of Dr. Doggett's independently funded lab devoted to anti-protozoan drug discovery for veterans and his infectious disease career as a physician with parasitology expertise devoted to the care of veterans.

疟疾是世界上死亡的主要原因之一。当前的疟疾疗法受到药物的限制 反抗。弓形虫弓形虫在全球范围内发现，并引起毁灭性眼病和脑炎。 目前对弓形虫病的疗法的耐受性不佳，不会消除其宿主的感染。退伍军人 在服兵役期间暴露于这些感染，新治疗将大大改善 退伍军人的健康。 Doggett博士和他的同事开发了新药，例如Quinolones（ELQ）， 对疟疾和T. gondii非常有效。他选择ELQ-316作为主要药物，因为它是 口服，无毒和高效。 Doggett博士在T. Gondii和 酿酒酵母的糖瘤表明ELQ抑制线粒体细胞色素BC1复合物（Cyt BC1）。 Doggett博士将测试ELQ-316抑制Cyt BC1并表征ELQ-316相互作用的假设 与Cyt BC1。他还将测试是否抑制CYT BC1的两个活性位点是否会降低恶性疟原虫的能力 发展耐药性。 Doggett博士将通过测量对抗性的速率来检验这一假设 ELQ-316与Atovaquone的组合以及ELQ-316对恶性疟原虫克隆的电阻率 那具有抗逆性的抗性。如果两个CYT BC1活性位点发生突变，他将测量催化 酶的活性。 Doggett博士将通过寻找协同作用来优化ELQ-316的管理 ELQ-316与临床使用的针对弓形虫病和疟疾的药物的组合，确定 ELQ-316的药代动力学口服和透射，并开发ELQ-316前药。 Doggett博士是俄勒冈州健康与科学大学和波特兰VA的传染病医师 医疗中心。他对被忽视的热带疾病的新疗法特别感兴趣 退伍军人。他已经在迈克·里斯科（Mike Riscoe 原生动物病原体中的耐药性。 Doggett博士已经熟练了生化和 他当前的研究计划所需的分子方法。 VA CDA-2奖将为博士提供。 Doggett进一步培训药代动力学，药物设计和计算机的新培训 基于分子建模。作为强大的培训计划的一部分，Doggett博士选择了一个高级小组 具有分子寄生虫学专业知识的科学家，T。Gondii，plasmodia，临床前药物开发和S。 Cerevesiae作为模型系统。该小组在指导早期调查人员方面经验丰富，并将与 Doggett博士每6个月正式正式。小组将提供有关实验，出版物和 职业发展。此外，Doggett博士将参加Woods Hole分子寄生虫学课程，参加 OHSU的科学课程，并在会议上介绍了他的研究。该奖项将在 建立Doggett博士的独立资助的实验室 以及他作为寄生虫专业知识的医生的传染病事业，致力于老兵的照顾。