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

• 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
• 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

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.

Babesiosis是在美国在世界范围内发现的一种类似疟疾的疾病。该疾病是引起的 由巴贝西亚属的肉体内寄生虫。 Babesia Microti和Babesia Duncani， 负责美国报告的大多数案件，由ixodes scapularis和 Dermacentor Albipictus tick虫，也可以通过输血引入。电流 人类巴氏病的治疗包括与阿托瓦喹酮+阿奇霉素的组合疗法或 克林霉素+奎宁。但是，这些药物与高复发率，治疗失败有关 和不利事件。此外，最近在感染了微芽孢杆菌和邓卡尼芽孢杆菌体外的小鼠的研究 表明这些寄生虫自然耐受这些药物。这些限制强调了需要 用于治疗人类Babesiosis的更有效，更安全的疗法。我们最近报告了 在人红细胞中为邓卡尼芽孢杆菌的连续体外培养系统的发展。使用此测定， 我们筛选了FDA批准的药物库，并鉴定出Fosinopril 羧肽酶ACE抑制剂fosinoprilat）作为有效的抗体抑制剂。该化合物也是 在以10 mg/kg为单位的小鼠模型中，对邓卡尼芽孢杆菌和小芽孢杆菌有效。有趣的是， fosinoprilat和其他ACE抑制剂均未影响邓卡尼在体外的生长。同样有趣， Fosinopril和Bortezomib的结构分析（在该中鉴定出的另一种有效的Duncani的有效抑制剂 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。 这些数据一起表明，佛辛opril的抗体活性可能是由于抑制任何一种 ace样肽酶和/或贝贝斯寄生虫的蛋白酶体活性。该应用程序的主要目标 鉴定具有更有效抗体但没有ACE活性的fosinopril的类似物，并阐明 这些化合物在巴贝西亚寄生虫中的作用机理。在我们的初步数据的基础上，我们 提出以下三个特定目标。在AIM 1中，我们将确定是否 fosinopril是活性化合物，表征了Fosinopril和新合成类似物的功效 反对邓卡尼（B. duncani）和小芽孢杆菌（B. microti）临床和现场分离株，并检查结构活性 这些寄生虫的关系。在AIM 2中，我们将表征最活跃的体内功效 单独或与其他药物结合使用，以消除贝贝西亚感染的策略。目标 3，我们将实施生化，质谱和遗传测定法，以阐明 贝贝西亚对佛辛顿及其类似物的抗性机制。提议的成功 三个目标将指导未来的临床试验，以创建一种理想的治疗人类Babesiosis的方案 没有复发。