Fosinopril analogs for the treatment of human babesiosis

福辛普利类似物用于治疗人类巴贝虫病

基本信息

批准号：
10211812
负责人：
CHOUKRI BEN MAMOUN
金额：
$ 74.28万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-21 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10211812
关键词：
Adverse event Affect Angiotensin-Converting Enzyme Inhibitors Animal Model Antihypertensive Agents Azithromycin Babesia Babesia microti Babesiosis Biochemical Biological Assay Biological Availability Black-legged Tick Blood Transfusion Borrelia microti Bortezomib Case Study Chemicals Clindamycin Clinical Clinical Trials Combined Modality Therapy Communicable Diseases Data Dermacentor Development Dipeptidyl Peptidases Disease Dose Drug Combinations Drug Kinetics Drug usage Erythrocytes Esters FDA approved Failure Formulation Future Genetic Genetic study Goals Growth Human Hybrids In Vitro Infection Knowledge Libraries Link Malaria Mass Spectrum Analysis Mus Parasites Parents Peptide Hydrolases Pharmaceutical Preparations Pharmacodynamics Prodrugs Property Proteasome Inhibitor Pyrimethamine Quinine Recrudescences Regimen Reporting Resistance Route Safety Serum Specificity Structure Structure-Activity Relationship System Therapeutic Therapeutic Index Ticks Treatment Failure Treatment Protocols United States analog atovaquone base design drug candidate effective therapy efficacy study esterase human model in vitro testing in vivo inhibitor/antagonist mouse model multicatalytic endopeptidase complex mutant pathogen peptidyl-dipeptidase Dcp pre-clinical research clinical testing side effect success tick-borne

项目摘要

Babesiosis is a malaria-like illness found worldwide and endemic in the United States. The disease is caused by intraerythrocytic parasites of the genus Babesia. Babesia microti and Babesia duncani, which are responsible for most cases reported in the United States, are transmitted to humans by Ixodes scapularis and Dermacentor albipictus ticks, respectively, and can also be introduced by blood transfusion. The current treatment for human babesiosis consists of combination therapies with atovaquone+azithromycin or clindamycin+quinine. However, these drugs are associated with high rate of recrudescence, treatment failures and adverse events. Furthermore, recent studies in mice infected with B. microti and in vitro with B. duncani showed that these parasites are naturally tolerant to these drugs. These limitations emphasize the need for more effective and safer therapies for treatment of human babesiosis. We have recently reported the development of a continuous in vitro culture system for B. duncani in human red blood cells. Using this assay, we screened a library of FDA-approved drugs and identified fosinopril (the prodrug of the dipeptidyl carboxypeptidase ACE inhibitor fosinoprilat) as a potent antibabesial inhibitor. The compound was also effective against both B. duncani and B. microti in mouse models of babesiosis at 10 mg/kg. Interestingly, neither fosinoprilat nor other ACE inhibitors affected the growth of B. duncani in vitro. Equally interesting, analysis of the structure of fosinopril and bortezomib (another potent inhibitor of B. duncani identified in the chemical screen and a known proteasome inhibitor) revealed similarities between the two compounds. Together these data suggest that the antibabesial activity of fosinopril could be due to inhibition of either an ACE-like peptidase and/or a proteasome activity of Babesia parasites. The primary goals of this application are to identify analogs of fosinopril with more potent antibabesial but no ACE activity, and to elucidate the mechanism of action of these compounds in Babesia parasites. Building upon our preliminary data, we propose the following three specific aims. In Aim 1, we will determine whether or not the prodrug form of fosinopril is the active compound, and characterize the efficacy of fosinopril and newly synthesized analogs against B. duncani and B. microti clinical and field isolates in vitro and examine the structure activity relationship specific to these parasites. In Aim 2, we will characterize the in vivo efficacy of the most active compounds alone or in combination with other drugs as a strategy for elimination of Babesia infections. In Aim 3, we will implement biochemical, mass spectrometry and genetic assays to elucidate the mode of action of and possible mechanisms of Babesia resistance to fosinopril and its analogs. The success of the proposed three aims will guide future clinical trials to create an ideal regimen for the treatment of human babesiosis with no recrudescence.

巴贝斯虫病是一种类似疟疾的疾病，在世界各地都有发现，在美国流行。该病是由引起的由巴贝虫属红细胞内寄生虫引起。田鼠巴贝斯虫 (Babesia microti) 和邓肯巴贝斯虫 (Babesia ducani) 造成美国报告的大多数病例的原因是肩胛硬蜱传播给人类白纹革蜱分别也可通过输血引入。目前的人类巴贝虫病的治疗包括阿托伐醌+阿奇霉素的联合疗法或克林霉素+奎宁。然而，这些药物与高复发率、治疗失败有关和不良事件。此外，最近对感染田鼠芽孢杆菌和体外感染邓氏芽孢杆菌的小鼠进行的研究表明这些寄生虫对这些药物具有天然耐受性。这些限制强调了需要治疗人类巴贝斯虫病的更有效和更安全的疗法。我们最近报道了开发人类红细胞中邓肯氏杆菌连续体外培养系统。使用该测定法，我们筛选了 FDA 批准的药物库并鉴定出福辛普利（二肽基的前药）羧肽酶 ACE 抑制剂福辛普利拉 (fosinoprilat) 是一种有效的抗巴贝虫抑制剂。该化合物还被 10 mg/kg 对巴贝斯虫病小鼠模型中的邓氏巴贝斯虫和田鼠巴贝斯虫均有效。有趣的是，福辛普利拉和其他 ACE 抑制剂均不影响 B. ducani 的体外生长。同样有趣的是，福辛普利和硼替佐米（B. ducani 的另一种有效抑制剂）的结构分析化学筛选和已知的蛋白酶体抑制剂）揭示了两种化合物之间的相似性。这些数据共同表明，福辛普利的抗巴贝虫活性可能是由于抑制巴贝虫寄生虫的 ACE 样肽酶和/或蛋白酶体活性。此应用程序的主要目标旨在鉴定具有更有效的抗巴贝虫作用但没有 ACE 活性的福辛普利类似物，并阐明这些化合物对巴贝虫寄生虫的作用机制。根据我们的初步数据，我们提出以下三个具体目标。在目标 1 中，我们将确定前药形式是否福辛普利是活性化合物，表征了福辛普利和新合成类似物的功效针对 B. ducani 和 B. microti 临床和现场分离的体外并检测其结构活性这些寄生虫特有的关系。在目标 2 中，我们将表征最活跃的药物的体内功效单独使用化合物或与其他药物组合作为消除巴贝虫感染的策略。瞄准 3、我们将进行生化、质谱和基因检测来阐明其作用方式巴贝虫对福辛普利及其类似物耐药的可能机制。提议的成功三个目标将指导未来的临床试验，以创建治疗人类巴贝斯虫病的理想方案无复发。