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Compounds that block a novel Candida albicans target

阻断新型白色念珠菌靶标的化合物

基本信息

批准号：
10320221
负责人：
JULIA R KOEHLER
金额：
$ 48.69万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320221
关键词：
Amphotericin Antifungal Agents Antifungal Therapy Antiviral Agents Binding Biological Biological Assay Candida Candida albicans Candidiasis Cell Wall Cell membrane Cell surface Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Chemicals Chemosensitization Clinical Collection Data Defect Development Disseminated candidiasis Dose Drug Efflux Drug Exposure Drug Kinetics Drug Targeting Engineering Ensure Enzymes FDA approved Fluorescence Foscarnet Fungal Drug Resistance Genetic Goals Gold Grant Growth Human Infection Inorganic Phosphate Transporter Ion Channel Lead Libraries Life Cycle Stages Micafungin Modeling Multi-Drug Resistance Mus Mycoses New Mexico Organ Oxidative Stress Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pharmacology Phase Property Proteins Reagent Reporter Resistance Resistance development Role Saccharomyces cerevisiae Sampling Signal Pathway Sirolimus Stress Structure Structure-Activity Relationship System Testing Toxic effect Triage Tube Universities Validation Virulence Virulence Factors Work analog attributable mortality chemical property design drug discovery efflux pump experimental study fungus high throughput screening in vivo inhibitor/antagonist inorganic phosphate interest lead candidate mouse model new therapeutic target novel pathogen pathogenic fungus pressure receptor resistance mechanism resistance mutation screening small molecule inhibitor

项目摘要

SUMMARY/ABSTRACT Candida albicans is the most common pathogen causing invasive fungal infections. These infections are dreaded complications of serious illnesses, and are estimated to lead to death in about 20% of patients. There are very few treatment options for fungal infections. This is because many cellular components whose function could be disrupted by drugs are similar between fungi and humans, leading to unacceptable toxicities to human cells. We have identified a potential drug target in C. albicans which has no human homologs, and whose inactivation leads to potentiation of drugs in 2 of the 3 major antifungal classes. This target is conserved among 3 phyla of pathogenic fungi, suggesting that small-molecule inhibitors could potentiate antifungal activity against other fungal pathogens. Because it is a cell-surface transporter, inhibitors of this target are not susceptible to a major multidrug-resistance mechanism of C. albicans, the induction of drug efflux pumps. Other features that render it impervious to development of resistance are that it is not an essential protein, diminishing the selective pressure during drug exposure, and that part of the mechanisms of action of its inhibitors may be its role in virulence activities of the fungus. Virulence factors like hyphal growth and oxidative stress resistance are not required during commensal growth, which comprises the majority of the C. albicans life cycle. We engineered a C. albicans strain in which inhibition of our target of interest induces GFP expression. This reporter strain is amenable to high-throughput screening using the HyperCyt platform developed at The University of New Mexico. We propose to screen library collections of chemically well-defined compounds with desirable physicochemical properties, and with existing data for other indications. Active compounds identified in the screen will be prioritized by their effect in potentiating the “gold standard” antifungal amphotericin, by their potency in blocking virulence factors (e.g. hyphal growth), as well as their toxicity window. In addition, prioritization will involve compound physicochemical properties, chemical tractability, and binding efficiencies using state-of-the-art post-screen triage approaches. Further validation tests will employ an engineered “test tube cell” Saccharomyces cerevisiae strain, in which the target is expressed at the plasma membrane as the only transporter of its substrate. Structure-activity relationships for chemotypes of prioritized hits will be established early. Hit-to-lead medicinal chemistry will be performed on prioritized hits with a focus on low host cell toxicity and physicochemical properties that support the advancement of compounds into in vivo pharmacokinetics and efficacy experiments. This project will provide high-quality lead compounds for further development as an antifungal potentiator, and potentially as a virulence-modifying single agent.

摘要/文摘