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Identification of CYP5122A1 inhibitors as chemical probes for Leishmania biology

鉴定 CYP5122A1 抑制剂作为利什曼原虫生物学化学探针

基本信息

批准号：
10061546
负责人：
Zhuo Michael Wang
金额：
$ 47.82万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-21 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10061546
关键词：
Affect Afghanistan Alleles Anabolism Azoles Binding Biochemical Biological Assay Biology Bite Case Study Chemicals Communicable Diseases Complex Country Crystallization Cutaneous Leishmaniasis Cytochrome P450 Dangerousness Disease Drug Targeting Enzyme Kinetics Enzymes Ergosterol Excision Exhibits Fluorescence Future Gene Deletion Gene Mutation Growth High Pressure Liquid Chromatography Human Hybrids Hypersensitivity Image Impairment Infection Iraq Ketoconazole Knock-out Laboratories Lanosterol Left Leishmania Leishmania donovani Leishmaniasis Life Ligand Binding Ligands Malaria Medical Metabolic Biotransformation Military Personnel Organ Organism Outcome Parasites Parasitic Diseases Pathogenicity Pathway interactions Pharmaceutical Preparations Phlebotominae Prodrugs Proteins Public Health Reaction Resistance Roentgen Rays Role Route Skin Sterols Structural Models Structure Testing Vaccines Visceral Leishmaniasis assay development base chemotherapy cost cytotoxicity drug discovery effective therapy high throughput screening inhibitor/antagonist innovation mortality new therapeutic target novel posaconazole screening side effect

项目摘要

Summary Human leishmaniasis is a devastating infectious disease caused by protozoan parasites belonging to the genus of Leishmania. The disease is found in more than 90 countries and responsible for an estimated 1-2 million new infections each year worldwide. Leishmaniasis is also common in returning U.S. military personnel from Iraq and Afghanistan, with more than two thousand cases reported since 2001. Leishmania parasites cause disfiguring skin sores (cutaneous leishmaniasis or CL) and life-threatening infection of vital internal organs (visceral leishmaniasis or VL). VL (~20% of all leishmaniasis cases) is the most dangerous and fatal form of the disease, with a mortality rate close to 100% if left untreated. It is the second most deadly parasitic disease in the world (after malaria). Despite being a serious public health problem in many endemic regions, there are no vaccines or preventative chemotherapies available for leishmaniasis control. Current antileishmanial drugs have limited efficacy, serious side effects and high cost. Hence, there is a major unmet medical need for safe and effective drugs against leishmaniasis. Leishmanial CYP5122A1 is a novel cytochrome P450 (CYP) enzyme that is essential for the survival of L. donovani, a major causative agent for VL. Independent and our own studies have led us to hypothesize that identification of selective CYP5122A1 inhibitors as chemical probes will allow elucidation of its important role in the ergosterol biosynthesis by Leishmania. To test our hypothesis, three specific aims are proposed to answer three main questions: 1) How do the biochemical roles of CYP5122A1 and CYP51 compare in the ergosterol biosynthesis pathway of Leishmania? 2) Can selective CYP5122A1 inhibitors be identified and validated? and 3) Are arylimidamides (AIAs) and/or AIA-azole hybrids potential chemical probes to help delineate biochemical roles of CYP5122A1 in Leishmania biology? Innovative experimental approaches will be employed in the proposed project, e.g., a new HPLC-MS/MS-based sterol assay, fluorescence-based CYP5122A1 and CYP51 inhibition assays, and cutting-edge high content imaging-based intracellular antileishmanial assays. If successful, our proposed project to identify novel CYP5122A1 inhibitors will elucidate this protein’s role in Leishmania biology and validate CYP5122A1 as a drug target. Such an outcome could have a major positive impact on long-term leishmaniasis control around the globe.

总结