Compounds that block a novel Candida albicans target

阻断新型白色念珠菌靶标的化合物

• 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
• 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

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/摘要 白色念珠菌是导致侵入性真菌感染的最常见病原体。这些感染是 严重疾病的可怕并发症，据估计约有20％的患者死亡。那里 真菌感染的治疗选择很少。这是因为许多功能的蜂窝组件 真菌和人类之间可能被药物破坏相似，从而导致对人的不可接受的毒性 细胞。我们已经确定了没有人类同源物的白色念珠菌中的潜在药物靶标的 失活导致在3个主要抗真菌类别中的2种中导致药物增强。这个目标在 3个病原真菌的门，表明小分子抑制剂可能具有潜在的抗真菌活性 其他真菌病原体。因为它是细胞表面转运蛋白，所以该靶标的抑制剂不容易受到A的影响 白色念珠菌的主要多药耐药机制，诱导药物外泵。其他功能 使抗性发展不可渗，是它不是必需的蛋白质，从而减少了选择性 药物暴露期间的压力以及其抑制剂作用机理的一部分可能是其在 真菌的毒力活动。菌丝生长和氧化应激抗性等毒力因素不是 在共生生长过程中所需的大部分是白色念珠菌生命周期。 我们设计了一种白色念珠菌菌株，其中抑制我们感兴趣的靶标会诱导GFP表达。这 记者应变适合使用在 新墨西哥大学。我们建议用 理想的物理属性，并具有其他指示的现有数据。确定的活性化合物 在屏幕上，将通过其在潜在的“金标准”抗真菌性两性霉素中的作用来优先考虑。 阻断病毒因子（例如菌丝生长）及其毒性窗口的效力。此外， 优先级将涉及复合物理特性，化学障碍和结合效率 使用最先进的屏幕后分类方法。进一步的验证测试将采用工程化的“测试 管细胞”酿酒酵母菌株，其中靶标在质膜上表达靶标 仅其基材的转运蛋白。优先访问的化学型的结构活性关系将是 提早建立。将对优先级命中进行命中至铅的药物，重点是低宿主 细胞毒性和物理特性支持化合物进化为体内 药代动力学和效率实验。该项目将为 作为抗真菌势剂的进一步发展，并有可能作为毒力调节单一药物。