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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：
10396069
负责人：
CHOUKRI BEN MAMOUN
金额：
$ 72.59万
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/10396069
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 mouse model multicatalytic endopeptidase complex mutant pathogen peptidyl-dipeptidase Dcp pre-clinical rational design 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，在世界范围内发现，在美国流行。疾病是由