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Structural Requirements for Sterol 14alpha-Demethylases

甾醇 14α-脱甲基酶的结构要求

基本信息

批准号：
9198559
负责人：
Galina I Lepesheva
金额：
$ 40.91万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9198559
关键词：
Achievement Address Adverse effects Agriculture Alcohols Aldehydes Alzheimer&apos s Disease Amino Acid Sequence Animal Model Antifungal Agents Aspergillus fumigatus Azoles Binding Biochemical Biological Biological Process Biological Response Modifier Therapy Catalysis Cells Chagas Disease Chemotherapy-Oncologic Procedure Cholesterol Clinical Clinical Trials Complex Custom Cytochrome P450 Data Development Disease Drug Design Drug Targeting Drug effect disorder Drug resistance Electron Transport Electrons Enzymes Ergosterol Family Formic Acids Funding Future Goals Growth Growth and Development function Human Industrial fungicide Infection Knowledge Lead Malignant Neoplasms Membrane Fluidity Membrane Proteins Minor Mixed Function Oxygenases Modification Molecular Mycoses NADPH-Ferrihemoprotein Reductase Oral Organism Outcome Parasites Peptides Permeability Pharmaceutical Preparations Pharmacology Phylogeny Phytosterols Plants Positioning Attribute Process Progress Reports Proteins Protozoa Public Health Publications Reaction Research Resistance Roentgen Rays Savings Sterol Biosynthesis Pathway Sterols Structure Testing Trypanosoma cruzi Visceral Visceral Leishmaniasis Voriconazole arm base cancer cell cancer type cell growth cell type chemotherapy cholesterol biosynthesis design drug candidate drug discovery electron donor fungus human disease inhibitor/antagonist insight killings member membrane biogenesis methyl group microbial novel novel therapeutics pathogen pharmacophore posaconazole prevent protein protein interaction public health relevance resistant strain scaffold screening

项目摘要

DESCRIPTION (provided by applicant) Sterol 14-demethylase (CYP51) is the monooxygenase that catalyzes a unique three step reaction (14- methyl 14-alcohol14-aldehyde14-demethylated product plus formic acid), removing the 14- methyl group from the cyclized sterol precursors. CYP51 is regarded as a possible evolutionary ancestor to all members of the currently existing P450 superfamily. The CYP51 reaction is required for biosynthesis of cholesterol in humans, ergosterol in eukaryotic microbial human pathogens (such as fungi and protozoa), and various phytosterols in plants. The vast majority of the sterols are utilized for the formation of viable eukaryotic membranes (fluidity, permeability, modulation of multiple functions of integrated membrane proteins), while some sterols serve as precursors for a number of regulatory molecules essential for cell growth, development, and multiplication. Blocking sterol biosynthesis in unicellular organisms is lethal. CYP51 inhibitors (azoles) are used as the major clinical antifungal drugs and agricultural fungicides. Two of these drugs (posaconazole and ravuconazole) are presently in clinical trials for the deadly human infection caused by the protozoan pathogen Trypanosoma cruzi (Chagas disease). All of the azoles currently in use were discovered empirically, i.e. by screening their effects on fungal cell growth, and are far from ideal in terms of efficiency, safet, side effects, and sensitivity to resistance. The long-term goal of our research is to understand the molecular basis for the CYP51 functional conservation, drug action, and drug resistance. Here we propose to apply the information on the CYP51 structure/function that was gained during the previous cycles of funding to rationalize the CYP51-targeting drug discovery paradigm. We will perform protozoan/fungal/human CYP51 structure-guided derivatization of the highly potent, non-toxic experimental VNI scaffold to make pharmacologically-optimized drug candidates suitable for clinical trials for Chagas disease (including the infections caused by naturally resistant strains of the parasite) and visceral leishmaniasis (Aim 1a), as well as to develop new custom-designed inhibitors of fungal CYP51s (Aim 1b). Aim 2 will evaluate human CYP51 as a potential drug target for cholesterol- related human diseases, including cancer and Alzheimer's disease. Aim 3 of this proposal is to determine the structure of CYP51 in complex with its electron donor partner, NADPH-cytochrome P450 reductase, which will reveal the key residues involved in the protein-protein interaction, and may lead to the development of a novel type of CYP51 inhibitors. The results of this research will direct future approaches in drug discovery, enabling the creation of rationally designed species-oriented drug candidates directed at saving millions of human lives.