Preclinical optimization of a parasiticidal drug for cryptosporidiosis

隐孢子虫病杀寄生虫药物的临床前优化

• 批准号: 10569660
• 负责人: CHRISTOPHER D HUSTON
• 金额: $ 69.98万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569660
• 关键词: ADME Study; Acceleration; Acquired Immunodeficiency Syndrome; Address; Adult; Affect; Animals; Antiparasitic Agents; Arrhythmia; Biliary; Biochemical; Biological Assay; Biology; Blood; CRISPR/Cas technology; Cardiotoxicity; Characteristics; Child; Chronic; Clinical; Cryptosporidiosis; Cryptosporidium; Cryptosporidium parvum; Cytochrome P450; Dairying; Diarrhea; Disease Outbreaks; Dissection; Dose; Drug Design; Drug Interactions; Drug Targeting; Drug resistance; Enzymes; Ethers; Europe; Excretory function; Exposure to; Future; Genes; Genetic; Gnotobiotic; Goals; Human; Immunocompromised Host; In Vitro; Infant; Infection; Intestines; Lead; Life; Malaria; Methods; Modeling; Molecular Mechanisms of Action; Molecular Target; Mus; Mutation; Oral; Outcome; Parasites; Patients; Periodicity; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phenotype; Piperazines; Placebos; Plasmodium; Potassium Channel; Property; Proteins; Public Health; Research; Resistance; Resources; Safety; Series; Small Intestines; Structure; Testing; Tissues; Toxic effect; Toxicology; Transplant Recipients; United States; Validation; Work; analog; chemical synthesis; chemoproteomics; clinical candidate; clinical development; clinical efficacy; diarrheal disease; drug candidate; drug development; drug discovery; enteric infection; genome sequencing; improved; in vitro Assay; in vivo; intestinal epithelium; lead optimization; manufacturing cost; mouse model; nitazoxanide; novel; patient population; pharmacokinetics and pharmacodynamics; porcine model; pre-clinical; programs; resistant Plasmodium falciparum; screening; success; waterborne; whole genome

PROJECT SUMMARY Cryptosporidiosis is amongst the most important causes of life-threatening diarrhea in children globally, causes incurable diarrhea in AIDS and transplant patients, and is the most common cause of waterborne diarrheal outbreaks in the United States. Almost all human cases of cryptosporidiosis are due to infection of the small intestinal epithelium with one of two species of Cryptosporidium parasites, C. parvum or C. hominis. Nitazoxanide, the only approved drug, is efficacious in otherwise healthy adults, but unfortunately, has limited efficacy (~56%) in children and is equivalent to a placebo in AIDS patients. The long-term goal of this research program is to develop improved drugs to treat cryptosporidiosis. In this project, a parasiticidal piperazine- based lead compound with extraordinary in vivo efficacy that was identified by phenotypic screening will be optimized, and its molecular mechanism of action will be determined. The lead optimization program is guided by an ideal target product profile and milestones to provide a pre-clinical lead that is likely to be effective in all patient populations affected by Cryptosporidium and has safety characteristics suitable for treatment of infants, minimal drug-drug interactions, minimal oral dosing requirements, stability in the tropics, and a low manufacturing cost. The methods for lead optimization bring together novel in vitro assays and a highly immunocompromised mouse model of cryptosporidiosis with well-established pharmacology and medicinal chemistry approaches. For this, cyclic rounds of chemical synthesis will be combined with in vitro Cryptosporidium assays, in vitro ADME studies, mouse PK studies, and a chronic mouse model of C. parvum infection. A piglet model will then be used to test clinical efficacy against C. hominis. The method for drug target identification will take advantage of the lead compound's activity against related malaria parasites to identify mutations associated with drug resistance and candidate drug targets, followed by CRISPR/Cas9 validation of mutations in C. parvum and biochemical methods to assess direct protein-drug interactions. Success would yield an optimized clinical candidate that is ready to be advanced to testing in regulatory toxicology studies, and a validated drug target that will accelerate drug development by enabling target-based drug design and target-based screening efforts to identify additional chemotypes. Given the dire need for new cryptosporidiosis drugs, the public health impact of success could be extremely significant.

项目摘要 隐孢子虫病是全球威胁儿童生命的腹泻的最重要原因之一， 艾滋病和器官移植患者的不治之症，也是水传播性腹泻最常见的原因 在美国爆发。几乎所有的人类隐孢子虫病病例都是由于感染了 肠上皮内寄生两种隐孢子虫之一，C. parvum或C.人类 硝唑尼特是唯一被批准的药物，对其他健康的成年人有效，但不幸的是， 在儿童中的有效性（~56%），在艾滋病患者中与安慰剂相当。这项研究的长期目标是 该计划是开发改进的药物来治疗隐孢子虫病。在这个项目中，一种杀寄生虫的哌嗪- 通过表型筛选鉴定的具有非凡体内功效的基于先导化合物的化合物， 优化，并确定其分子作用机制。引导引导优化程序 通过一个理想的目标产品概况和里程碑，提供一个临床前的领导，可能是有效的， 受隐孢子虫感染的患者群体，并且具有适合于治疗婴儿的安全特征， 最小的药物-药物相互作用，最小的口服给药要求，在热带地区的稳定性，以及低的 制造成本。用于先导物优化的方法将新颖的体外测定和高度生物相容性结合在一起。 隐孢子虫病免疫受损小鼠模型具有良好的药理学和药物学基础 化学接近。为此，循环的化学合成将与体外合成相结合。 隐孢子虫试验、体外ADME研究、小鼠PK研究和慢性C. parvum 感染然后将使用仔猪模型来测试针对C的临床功效。人类药物的方法 目标鉴定将利用先导化合物对相关疟疾寄生虫的活性， 确定与耐药性和候选药物靶点相关的突变，然后进行CRISPR/Cas9 C.突变的验证。parvum和生物化学方法来评估直接的蛋白质-药物相互作用。 成功将产生一个优化的临床候选药物，准备在监管部门进行测试 毒理学研究，以及一个经过验证的药物靶点，通过实现基于靶点的 药物设计和基于靶点的筛选工作，以确定其他化学型。鉴于迫切需要新的 隐孢子虫病药物，成功的公共卫生影响可能是极其显著的。

项目成果

Structure-Activity relationships of replacements for the triazolopyridazine of Anti-Cryptosporidium lead SLU-2633.

抗隐孢子虫先导物 SLU-2633 的三唑并哒嗪替代物的构效关系。

• DOI: 10.1016/j.bmc.2023.117295
• 发表时间: 2023
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: Oboh,Edmund;Teixeira,JoséE;Schubert,TannerJ;Maribona,AdrianaS;Denman,BrylonN;Patel,Radhika;Huston,ChristopherD;Meyers,MarvinJ
• 通讯作者: Meyers,MarvinJ

Structure-Activity Relationship Studies of the Aryl Acetamide Triazolopyridazines against Cryptosporidium Reveals Remarkable Role of Fluorine.

芳基乙酰胺三唑并哒嗪抗隐孢子虫的构效关系研究揭示了氟的显着作用。

• DOI: 10.1021/acs.jmedchem.3c00110
• 发表时间: 2023
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Schubert,TannerJ;Oboh,Edmund;Peek,Hannah;Philo,Emily;Teixeira,JoséE;Stebbins,ErinE;Miller,Peter;Oliva,Jonathan;Sverdrup,FrancisM;Griggs,DavidW;Huston,ChristopherD;Meyers,MarvinJ
• 通讯作者: Meyers,MarvinJ

Optimization of the Urea Linker of Triazolopyridazine MMV665917 Results in a New Anticryptosporidial Lead with Improved Potency and Predicted hERG Safety Margin.

• DOI: 10.1021/acs.jmedchem.1c01136
• 发表时间: 2021-08-12
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Oboh E;Schubert TJ;Teixeira JE;Stebbins EE;Miller P;Philo E;Thakellapalli H;Campbell SD;Griggs DW;Huston CD;Meyers MJ
• 通讯作者: Meyers MJ