Development of new drugs for Toxoplasma by advancing hits from the Global Health Chemical Diversity Library

弓形虫是一种真核寄生虫，广泛分布于世界各地。感染 感染弓形虫可导致严重和潜在致命的脑部和眼部疾病，特别是在免疫功能低下的情况下。 个人。在世界范围内，弓形虫也是导致其他健康人失明的主要传染病原因。 目前治疗弓形虫的fi一线疗法是乙胺嘧啶和磺胺嘧啶的组合，但 这种养生法有许多缺点。这些药物必须服用几周到几个月， 经常引起毒副作用，无法根除慢性感染。我们需要新药 对于弓形虫来说，这些药物更安全、耐受性更好、更有效，并且可以更短的持续时间。 为此，阿尔代博士和他的同事们在《全球健康》杂志上筛选了68689种化合物 fi的化学多样性文库和抑制弓形虫生长的那些。在这样做的过程中，359次命中 发现有强烈抑制该寄生虫生长的化合物。其中每一项的效力都是 测量了73种高效和选择性化合物的子集，并选择进行进一步研究。所有化合物 在GHCDL中被选中是因为它们的类似药物的物理化学性质预测良好的吸收和 口服时的分布。因此，似乎有理由假设，在359种化合物中 强烈抑制弓形虫生长的是那些口服后能有效对抗弓形虫病的药物 因此，开发新药的起点很好。奥尔代博士的研究将系统地 从三个方面对这一假设进行评估。首先，将对所有73种化合物的效力进行验证。关于…的初步研究 将完成这三个最有希望的化合物的结构-活性关系。其次，阿尔代博士将决定 最有希望的10种化合物的作用机制是通过产生抗性突变体和 使用全基因组测序识别相关突变。最后，前十名的有效性 化合物将在感染的小鼠模型中进行测试。 奥尔代博士是俄勒冈健康与科学大学和波特兰退伍军人医学中心的内科科学家 中心。临床上，他接受了内科和传染病(ID)的培训，轮换住院ID 提供会诊服务，并设有门诊部。他的博士学位是生物化学，重点是物理 蛋白质-蛋白质和蛋白质-小分子相互作用的化学。这种不同寻常的背景给了他一个 用于开展CDA应用程序中描述的工作的强大背景。他曾在 波特兰VAMC实验化疗实验室与Michael Riscoe博士和Stone Doggett博士在过去 三年来，在评估药物和生物化学方法所需的分子和生化方法方面开发fi准确性 它们在原生动物寄生虫中的作用机制。这项CDA中提议的工作将为Alday博士提供 他需要在药物设计、药物机制评估和体内fi研究方面进行进一步的培训 成为一名独立的退伍军人事务部调查员。作为这笔培训拨款的一部分，他组建了一支高级团队 科学家和内科医生--在分子寄生虫学和药物开发方面有专长的科学家。总而言之， 他们已经指导了数十名学员走向独立。该小组将每六个月举行一次正式会议。 回顾阿尔代博士的进展。此外，该小组还将提供有关实验方法的意见， 在发表前审阅稿件，并就职业发展提出建议。阿尔代医生会带着 药代动力学和基因组测序方面的研究生课程，并在Sciencefic发表他的工作。 开会。在CDA结束之前，Alday博士将鉴定fi有希望的先导化合物，为 在药物开发道路上取得进展，以及未来药物开发努力的新目标。 将这些线索向前推进将构成退伍军人事务部功绩审查和NIH R01拨款申请的基础，这些申请将 使他成为一名独立的临床医生-科学家，致力于照顾fl感染性疾病的退伍军人 通过服务和研究传播疾病。

Toxoplasma gondii is a prolific eukaryotic parasite that is widely distributed throughout the world. Infection with T. gondii can cause severe and potentially fatal brain and eye disease, especially in immunocompromised individuals. Worldwide, T. gondii is also a leading infectious cause of blindness in otherwise healthy individuals. The current first-line therapy for T. gondii is a combination of the drugs pyrimethamine and sulfadiazine, but this regimen suffers from a number of shortcomings. These drugs must be taken for weeks to months, frequently cause toxic side effects, and are incapable of eradicating chronic infection. We need new medicines for T. gondii that are safer, better tolerated, more effective, and can be given for shorter durations. To this end, Dr. Alday and his colleagues have screened the 68,689 compounds in the Global Health Chemical Diversity Library (GHCDL) to find those that inhibit the growth of T. gondii. In doing so, 359 hit compounds were found that strongly inhibit the growth of this parasite. The potency of each of these has been measured and a subset of 73 highly potent and selective compounds selected for further study. All compounds in the GHCDL were chosen for their drug-like physicochemical properties that predict good absorption and distribution when taken orally. Therefore it seems reasonable to hypothesize that within the 359 compounds that strongly inhibit T. gondii growth are those that will be effective against toxoplasmosis when given orally and thus excellent starting points from which to develop new drugs. Dr. Alday's research will systematically evaluate this hypothesis in three parts. First, the potency of all 73 compounds will be verified. An initial study of the structure-activity relationships of the three most promising will be done. Secondly, Dr. Alday will determine the mechanism of action for the top 10 most promising compounds by creating resistant mutants and identifying relevant mutations using whole-genome sequencing. Finally, the effectiveness of the top 10 compounds will be tested in mouse models of infection. Dr. Alday is a physician-scientist at Oregon Health & Science University and the Portland VA Medical Center. Clinically, he is trained in internal medicine and infectious disease (ID), rotates on the inpatient ID consult service, and has an outpatient ID clinic. His PhD is in biochemistry, with a focus on the physical chemistry of protein-protein and protein-small molecule interactions. This unusual background gives him a strong background from which to pursue the work described in this CDA application. He has worked in the Portland VAMC Experimental Chemotherapy Lab with Dr. Michael Riscoe and Dr. Stone Doggett over the past three years, developing proficiency in the molecular and biochemical methods needed to evaluate drugs and their mechanism of action in protozoan parasites. The work proposed in this CDA will provide Dr. Alday with further training in drug design, evaluation of drug mechanisms, and in vivo efficacy studies he needs to become an independent VA investigator. As part of this training grant, he has assembled a team of senior scientists and physician-scientists with expertise in molecular parasitology and drug development. Collectively, they have mentored dozens of trainees towards independence. This panel will meet formally every six months to review Dr. Alday's progress. Additionally, this panel will provide input regarding experimental approaches, review manuscripts prior to publication, and give advise about career development. Dr. Alday will take graduate-level classes in pharmacokinetics and genome sequencing and present his work at scientific meetings. Prior to the end of this CDA, Dr. Alday will have identified promising lead compounds ready for advancement down the drug development pathway as well as new targets for future drug development efforts. Moving these leads forward will form the basis for VA Merit Review and NIH R01 grant applications that will establish him as an independent clinician-scientist devoted to caring for veterans afflicted by infectious diseases through service and research.