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

疟疾是世界上主要的死亡原因之一。目前的疟疾治疗受到药物的限制 阻力弓形虫在世界范围内都有发现，它能引起毁灭性的眼病和脑炎。 目前治疗弓形虫病的耐受性差，不能根除宿主的感染。退伍军人 在服兵役期间暴露于这些感染，新的治疗方法将大大改善 退伍军人的健康Doggett博士和他的同事们开发了新的药物，类似于喹诺酮类药物（ELQ）， 对疟疾和T.刚地。他选择ELQ-316作为主要药物，因为它是 口服、无毒、高效。道吉特博士在T.弓形虫和 酿酒酵母表明，ELQs抑制线粒体细胞色素bc 1复合物（cyt bc 1）。 Doggett博士将检验ELQ-316抑制cyt bc 1的假设，并描述ELQ-316如何相互作用 与Cyt BC 1。他还将测试抑制细胞色素bc 1的两个活性位点是否会降低恶性疟原虫的能力， 产生抗药性。道吉特博士将通过测量对细菌的耐药性来检验这一假设。 ELQ-316与阿托伐醌的组合以及ELQ-316对恶性疟原虫克隆的抗性率 对阿托伐醌有抗药性如果突变发生在细胞色素bc 1的两个活性位点，他将测量细胞色素bc 1的催化活性。 酶的活性。Doggett博士将优化ELQ-316的给药， ELQ-316与临床使用的抗弓形虫病和疟疾的药物的组合， 本发明的目的在于研究ELQ-316口服和经皮的药代动力学，以及开发ELQ-316前药。 Doggett博士是俄勒冈州健康与科学大学和波特兰弗吉尼亚州的传染病医生 医学中心他特别感兴趣的是被忽视的热带疾病的新疗法， 老兵他在Mike Riscoe博士的实验室进行了研究，调查药物的作用机制， 原生动物病原体的抗药性。道根博士精通生物化学， 他目前的研究计划所需要的分子方法。VA CDA-2奖将提供博士。 Doggett药物机制的进一步培训和药代动力学，药物设计和计算机的新培训 基于分子模型的作为一个强大的培训计划的一部分，道根博士已经选择了一个小组的高级 具有分子寄生虫学专业知识的科学家T.弓形虫、疟原虫、临床前药物开发和S. cerevesiae作为一个模型系统。该小组在指导早期调查人员方面经验丰富，并将与 博士道根每6个月正式。该小组将提供有关实验，出版物和 职业发展。此外，道格特博士将参加伍兹霍尔分子寄生虫学课程，参加 科学课程，并在会议上介绍他的研究。该奖项将在 Doggett博士独立资助的实验室的建立，致力于为退伍军人发现抗原生动物药物 以及他作为一名具有寄生虫学专业知识的医生致力于照顾退伍军人的传染病职业生涯。

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.