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

通过推进全球健康化学多样性图书馆的热门产品开发治疗弓形虫的新药

• 批准号: 9891756
• 负责人: Phil Holland Alday
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891756
• 关键词: Anti-Infective Agents; Antibiotics; Applications Grants; Biochemical; Biochemistry; Biology; Blindness; Brain; Brain Diseases; CRISPR/Cas technology; Caring; Cells; Cessation of life; Chemicals; Clinic; Clinical; Communicable Diseases; Consult; Cyst; Data; Development; Diversity Library; Doctor of Philosophy; Dose; Drug Combinations; Drug Design; Drug Evaluation; Drug Kinetics; Drug resistance; Effectiveness; Essential Genes; Evaluation; Eye diseases; Future; Genetic; Genome; Grant; Growth; HIV; Health Benefit; Health Sciences; Health Services Research; Healthcare Systems; Human; Immunocompromised Host; Immunosuppression; Individual; Infection; Inpatients; Internal Medicine; K-Series Research Career Programs; Knock-out; Lead; Libraries; Manuscripts; Measures; Medical; Medical center; Medicine; Mentors; Methods; Molecular; Monitor; Mutagenesis; Mutation; Open Reading Frames; Oral; Oregon; Organ; Outpatients; Parasites; Parasitic infection; Parasitology; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Physical Chemistry; Physicians; Population; Positioning Attribute; Property; Protein Chemistry; Proteins; Protozoa; Publications; Pyrimethamine; Regimen; Research; Research Personnel; Resistance; Resources; Risk; Savings; Scientist; Senior Scientist; Serum; Services; Single Nucleotide Polymorphism; Site-Directed Mutagenesis; Solid; Source; Stem cell transplant; Structure; Structure-Activity Relationship; Sulfadiazine; System; Testing; Time; Tissues; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Training; Transplantation; United States National Institutes of Health; Universities; Veterans; Work; absorption; acute infection; career development; chemotherapy; chronic infection; disability; drug development; drug mechanism; drug testing; effectiveness testing; efficacy study; experimental study; forward genetics; genetic approach; genome sequencing; global health; immunosuppressed; improved; in vivo; in vivo imaging system; infection burden; insight; latent infection; meetings; member; mouse model; mutant; new therapeutic target; novel; novel therapeutics; pressure; prevent; prophylactic; reactivation from latency; resistant strain; side effect; small molecule; whole genome

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.

弓形虫是一种多产的真核寄生虫，广泛分布于世界各地。感染 和t.弓形虫可导致严重的和潜在致命的脑部和眼部疾病，特别是在免疫功能低下的患者中， 个体全世界，T。弓形虫也是导致健康个体失明的主要传染性原因。 目前T.弓形虫是乙胺嘧啶和磺胺嘧啶的混合药物， 该方案存在许多缺点。这些药物必须服用数周至数月， 经常引起毒副作用，并且不能根除慢性感染。我们需要新药 对于T.更安全，耐受性更好，更有效，并且可以在更短的时间内给予。 为此，Alday博士和他的同事们对全球卫生组织（Global Health）的68，689种化合物进行了筛选。 化学多样性库（GHCDL）来寻找那些抑制T。刚地。在这样做的时候，359击中 发现了强烈抑制这种寄生虫生长的化合物。每一种药物的效力 测量并选择73种高效和选择性化合物的子集进行进一步研究。所有化合物 在GHCDL中，选择它们的药物样理化性质，预测良好的吸收， 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T.弓形虫生长是那些口服给药时对弓形虫病有效的 因此也是开发新药的良好起点。阿尔代博士的研究将系统地 分三个部分来评估这个假设。首先，将对所有73种化合物的效价进行验证艾德。的初步研究 对其中最有前途的三种化合物进行构效关系研究。其次，阿尔代医生会决定 通过产生耐药突变体来研究十大最有前途的化合物的作用机制， 使用全基因组测序鉴定相关突变。最后，前10名的有效性 将在小鼠感染模型中测试化合物。 Alday博士是俄勒冈州健康与科学大学和波特兰退伍军人医疗中心的医生兼科学家 中心临床上，他接受过内科和传染病（ID）培训，在住院ID上轮换 咨询服务，并有一个门诊ID诊所。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。这种不寻常的背景给了他一个 强大的背景，从追求本CDA应用程序中描述的工作。曾任职于 波特兰VAMC实验化疗实验室与博士迈克尔Riscoe和博士斯通Doggett过去 三年，发展评估药物所需的分子和生物化学方法的专业知识， 它们在原生动物寄生虫中的作用机制。本CDA中提出的工作将为Alday博士提供 他需要在药物设计、药物机制评估和体内有效性研究方面进行进一步培训， 成为独立的调查员。作为培训补助金的一部分，他组建了一个高级 在分子寄生虫学和药物开发方面具有专长的科学家和医生科学家。总的来说， 他们指导了数十名受训者走向独立。该小组将每六个月举行一次正式会议 检查一下阿尔戴医生的进展此外，该小组将提供关于实验方法的投入， 在出版前审阅稿件，并对职业发展提出建议。艾尔戴医生会 研究生水平的药物代谢动力学和基因组测序课程，并介绍了他在科学 会议.在本CDA结束之前，Alday博士将确定有希望的先导化合物，准备用于 药物开发途径的进展以及未来药物开发工作的新目标。 将这些线索向前推进将构成VA Merit Review和NIH R01赠款申请的基础， 使他成为一名独立的临床医生-科学家，致力于照顾感染性疾病的退伍军人。 通过服务和研究。