Targeting Hsp90 in cryptococcal fungal pathogenesis

隐球菌真菌发病机制中的靶向 Hsp90

基本信息

批准号：
9171395
负责人：
Lauren Elaine Brown
金额：
$ 80.44万
依托单位：
UNIVERSITY OF TORONTO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-15 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9171395
关键词：
Affinity Animals Antifungal Agents Aspergillus Azole resistance Azoles Binding Biochemical Biological Biological Assay Biological Process Biology Candida Candida albicans Cell Communication Cells Cessation of life Chemicals Chemistry Clinical Complement Coupled Cryptococcal Meningitis Cryptococcus Cryptococcus gattii Cryptococcus neoformans Cryptococcus neoformans infection Development Disease Disease Outbreaks Diversity Library Dose-Limiting Drug Kinetics Drug resistance Economics Eukaryota Fluorescence Polarization Fungal Drug Resistance Future Genetic Goals HIV Health Heat-Shock Proteins 90 Human Immunocompromised Host In Vitro Individual Industrial fungicide Infection Investigational Therapies Lead Left Libraries Malignant Neoplasms Measures Medical Melanins Molecular Molecular Chaperones Mus Mycoses N-terminal Natural Products Nucleotides Organ Transplantation Organism Oximes Pacific Northwest Pathogenesis Pharmaceutical Preparations Pharmacology Production Proteins Resistance Resources Role Route Sepsis Specificity Stress Structure Structure-Activity Relationship System Testing Therapeutic Therapeutic Intervention Toxic effect Virulence Work abstracting acquired drug resistance analog base brain endothelial cell burden of illness cancer therapy capsule clinical care design drug candidate drug metabolism effective therapy frontier fungus immune function improved in vivo inhibitor/antagonist insight macrophage microorganism monorden mortality mouse model multidisciplinary novel pathogen promoter small molecule targeted treatment tool trait

项目摘要

Project Summary/Abstract Intrinsic and acquired drug resistance of medically relevant microorganisms poses a grave threat to human health and has enormous economic consequences worldwide. Fungal pathogens present a particular challenge because they are eukaryotes and share many of the same biological processes as the human hosts they infect. Among the most pervasive fungal pathogens are species of Cryptococcus, which cause over 600,000 deaths per year. Cryptococcal meningitis, the major clinical manifestation of the disease, has a 100% mortality rate if left untreated. Even with the best available therapies, mortality rates remain high at 35-40% because the number of drug classes that have distinct targets in fungi is very limited and the usefulness of current antifungal drugs is compromised by either dose-limiting host toxicity or the frequent emergence of high- grade resistance. New, non-cross-reactive targets for therapeutic intervention are urgently needed. In previous work, we discovered that that the molecular chaperone Hsp90 regulates drug resistance and virulence in species of the fungi Candida and Aspergillus. Targeting Hsp90 in these pathogens promises to provide a powerful strategy to enhance the efficacy of antifungal drugs and abrogate drug resistance, but the role of Hsp90 in pathogenic cryptococcal species remains unexplored. The “druggability” of Hsp90 has been well established by the many small molecules targeting this protein for the treatment of human cancers. The poor antifungal activity and likely toxicity of currently available drugs in the setting of fungal infection, however, demand the development of fungal-selective Hsp90 inhibitors. To pursue the goal of fungal selectivity, our interdisciplinary team solved the structure of the N-terminal domain of Candida albicans Hsp90, and identified a pocket in the nucleotide-binding region that is larger than its human counterpart and is conserved in Cryptococcus. Guided by this insight, we designed, synthesized and characterized two lead inhibitors of fungal Hsp90 with >10-fold selectivity relative to the human protein. Now, leveraging the novel chemistry and structure-based design approach we have developed, we will use our complementary expertise in fungal biology (Cowen), chemistry (Brown), and pharmacology/experimental therapeutics (Whitesell) to pursue structure activity relationship (SAR) studies on libraries of additional analogs and generate selective drug-like probes. These will be used in a powerful combination of genetic and pharmacological approaches to dissect Hsp90's role in the drug resistance and virulence of Cryptococcus. In addition to the important basic insights that will be obtained, our results are likely to impact the treatment of invasive fungal infections in the near future by providing promising leads for the development of drug candidates that operate in a completely unexploited target space.

项目摘要/摘要医学上相关微生物的内在和获得的耐药性对人的威胁构成严重威胁健康，在全球范围内造成巨大的经济后果。真菌病原体提出了一个特定的挑战是因为它们是真核生物，并且与人类宿主共享许多相同的生物学过程他们感染了。最普遍的真菌病原体之一是加密赛物种，这会导致每年60万人死亡。该疾病的主要临床表现，隐球菌脑膜炎的脑膜炎有100％如果未治疗，死亡率。即使采用最佳疗法，死亡率仍然很高，为35-40％因为真菌中具有不同靶标的药物类的数量非常有限，并且有用的有用性剂量限制宿主毒性或经常出现高 - 等级抵抗。迫切需要进行新的非交叉反应性靶标。在先前的工作中，我们发现分子伴侣HSP90调节耐药性和真菌念珠菌和曲霉物种的毒力。在这些病原体中靶向HSP90有望提供有力的策略来提高抗真菌药物的效率并消除耐药性，但 HSP90在致病性隐球菌中的作用仍然出乎意料。 HSP90的“可药物性”已经针对该蛋白的许多小分子以治疗人类癌症来确定。然而要求开发真菌选择性HSP90抑制剂。为了追求真菌选择性的目标，我们的跨学科团队解决了N末端领域的结构白色念珠菌HSP90的念珠菌，并在核苷酸结合区域中确定了一个大于其大于其的口袋人类对应物，并在加密赛中配置。在这种见解的指导下，我们设计，合成和表征了两个真菌HSP90的铅抑制剂，相对于人类蛋白质，其选择性> 10倍。现在，利用我们开发的新型化学和基于结构的设计方法，我们将使用我们的真菌生物学（Cowen），化学（棕色）和药物/实验性的完全专业知识治疗（Whitesell）购买结构活动关系（SAR）研究的其他类似物的库并产生类似药物的问题。这些将用于遗传和药理学方法是剖析HSP90在加密赛中耐药性和病毒中的作用。在除了将获得的重要基本见解之外，我们的结果可能会影响治疗在不久的将来，通过提供毒品开发的诺言，在不久的将来进行侵入性真菌感染在完全出乎意料的目标空间中运作的候选人。