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。目前疟疾的治疗受到药物的限制。 抵抗。弓形虫在世界各地都有发现，会导致毁灭性的眼病和脑炎。 目前的弓形虫病治疗方法耐受性差，不能根除宿主的感染。退伍军人 在服兵役期间接触到这些感染，新的治疗方法将大大改善 退伍军人健康。道格特博士和他的同事们已经开发出新药，内分泌类似喹诺酮类药物(ELQ)， 对疟疾和弓形虫非常有效。他选择ELQ-316作为先导药物，因为它是 口服，无毒，高效。道格特博士在弓形虫和 酿酒酵母表明ELQs抑制线粒体细胞色素Bc1复合体(CytBc1)。 道格特博士将检验ELQ-316抑制Cyt bc1的假设，并描述ELQ-316如何相互作用 与Cyt Bc1结合。他还将测试抑制Cyt Bc1的两个活性部位是否会降低恶性疟原虫 产生抗药性。道格特博士将通过测量对这种病毒的抵抗率来检验这一假设。 ELQ-316与阿托瓦酮的联合应用及ELQ-316对恶性疟原虫克隆的耐药率 这对阿托瓦酮有抵抗力。如果两个细胞色素bc1活性部位都发生突变，他将测量催化 酶的活性。道格特博士将通过寻找协同作用来优化ELQ-316的管理 ELQ-316与临床上使用的治疗弓形虫病和疟疾的药物联合使用，确定 ELQ-316口服和经皮给药的药代动力学，并开发ELQ-316前药。 道格特博士是俄勒冈健康与科学大学和波特兰退伍军人管理局的传染病内科医生 医疗中心。他对被忽视的热带疾病的新疗法特别感兴趣，这些疾病 退伍军人。他在迈克·里斯科博士的实验室进行了研究，研究了药物的作用机制和 原生动物病原体的耐药性。道格特博士已经精通了生化和 他目前的研究计划所需要的分子方法。退伍军人事务部CDA-2奖将为Dr。 Doggett在药物机制方面的进一步培训以及在药物动力学、药物设计和计算机方面的新培训 基于分子建模。作为一项强有力的培训计划的一部分，道格特博士挑选了一组高年级学生 在分子寄生虫学、弓形虫、疟原虫、临床前药物开发和S. Cerevesiae作为模式系统。该小组在指导早期调查人员方面经验丰富，将会见 道根医生每6个月正式接受一次治疗。该小组将提供关于实验、出版物和 职业发展。此外，道格特博士还将参加伍兹霍尔分子寄生虫学课程，参加 在俄亥俄州立大学学习科学课程，并在会议上发表他的研究成果。这一奖项最终将在 道格特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 他的传染病职业生涯是一名内科医生，拥有致力于照顾退伍军人的寄生虫学专业知识。

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.