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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：
10669803
负责人：
Lauren Elaine Brown
金额：
$ 65.52万
依托单位：
UNIVERSITY OF TORONTO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-21 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10669803
关键词：
Achievement Address Affect Affinity Animals Antifungal Agents Antifungal Antibiotics Azoles Bacterial Infections Binding Biochemical Biological Assay Biological Process Biology Candida albicans Cells Cessation of life Chemicals Chemistry Clinical Collaborations Computational algorithm Conserved Sequence Cryptococcal Meningitis Cryptococcus Cryptococcus neoformans Development Disease Dose Dose Limiting Drug Kinetics Drug resistance Economics Eukaryota Funding Future Genomics Goals HIV HSP 90 inhibition Health Human Infection Investigation Lead Learning Left Life Longevity Machine Learning Malaria Malignant Neoplasms Maps Measures Metabolic Methods Modeling Molecular Biology Molecular Chaperones Molecular Conformation Molecular Medicine Molecular Target Monitor Mus Mycoses N-terminal National Institute of Allergy and Infectious Disease Nucleotides Organ Transplantation Outcome Pathogenesis Pathogenicity Persons Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Population Property Proteins Regimen Resistance Resource-limited setting Route Schedule Sepsis Structure Structure-Activity Relationship Testing Therapeutic Intervention Time Toxic effect Tuberculosis Work acquired drug resistance analog blood-brain barrier permeabilization burden of illness cancer therapy design drug candidate drug structure experience flexibility fungus immune function improved in vitro Assay inhibitor insight lead optimization microorganism mortality mouse model multidisciplinary pathogenic fungus pharmacologic pre-clinical preservation resistance mechanism small molecule standard of care targeted treatment

项目摘要

Summary/Abstract Intrinsic and acquired drug resistance of pathogenic 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 problematic fungal pathogens are species of Cryptococcus, which cause over 180,000 deaths per year across the globe. Cryptococcal meningitis, the major clinical manifestation of the disease, has a 100% mortality rate if left untreated. Even with best available therapies, mortality rates remain high 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 work performed with prior support from NIAID, we have shown that targeting the molecular chaperone Hsp90 in Cryptococcus and other fungi provides a powerful strategy to enhance the efficacy of antifungal drugs and abrogate drug resistance. The “druggability” of Hsp90 has been well established by many small molecules targeting this protein for the treatment of human cancers. The poor antifungal activity and toxicity of currently available drugs, however, demand development of fungal-selective inhibitors as proposed in this revised resubmission. To pursue the goal of fungal selectivity, our interdisciplinary team has now solved the structure of the drug- binding domain of Candida albicans and Cryptococcus neoformans Hsp90, both in unbound and inhibitor-bound states. These chemo-structural studies identified fungal-specific differences in conformational flexibility that allowed us to design, synthesize and characterize fungal-selective inhibitors of a new chemical class. Now, leveraging the new chemistry and structure-based design approaches we developed with previous funding, we will use our complementary expertise in fungal chemical and molecular biology (Cowen) and medicinal chemistry (Brown) to continue pursuing structure activity relationship (SAR) studies, but now augmented by newly developed computational algorithms to generate inhibitors with broad-spectrum antifungal activity. The efficacy of compounds alone and in combination with a standard antifungal will be tested in culture and in mice against drug-resistant C. albicans and C. neoformans. In addition to generating important basic insights, our results are likely to impact the treatment of invasive fungal infections in the near future by providing promising leads for development of actual antifungal drug candidates that operate in a new way.

总结/摘要病原微生物的内在和获得性耐药性对人类健康构成严重威胁，在全球范围内产生了巨大的经济影响。真菌病原体提出了一个特殊的挑战，它们是真核生物，与它们感染的人类宿主有许多相同的生物过程。之间最成问题的真菌病原体是隐球菌属，每年导致超过180，000人死亡遍布地球仪。隐球菌性脑膜炎是该病的主要临床表现，病死率高达100% 率，如果不治疗。即使有最好的治疗方法，死亡率仍然很高，因为药物的数量在真菌中具有不同靶点的抗真菌药物种类非常有限，受到剂量限制性宿主毒性或频繁出现的高级抗性的影响。新的，非- 迫切需要用于治疗干预的交叉反应靶点。在NIAID先前的支持下进行的工作中，我们已经表明，靶向分子伴侣Hsp90 在隐球菌和其他真菌提供了一个强有力的战略，以提高抗真菌药物的疗效，消除耐药性。Hsp90的"可药用性"已经被许多小分子很好地确立靶向这种蛋白质用于治疗人类癌症。目前的抗真菌活性和毒性较差，然而，现有的药物需要开发真菌选择性抑制剂，正如本修订版中所建议的那样，重新提交为了追求真菌选择性的目标，我们的跨学科团队现在已经解决了药物的结构- 白色念珠菌和新型隐球菌Hsp90的结合结构域，无论是未结合的还是结合的 states.这些化学结构研究确定了真菌特有的构象灵活性差异，使我们能够设计，合成和表征一种新的化学类别的真菌选择性抑制剂。现在我想，利用我们利用以前的资金开发的新的化学和基于结构的设计方法，我们将利用我们在真菌化学和分子生物学（考恩）和药物化学方面的互补专业知识（布朗）继续进行结构活性关系（SAR）研究，但现在增加了新的开发了计算算法来产生具有广谱抗真菌活性的抑制剂。疗效单独的化合物和与标准抗真菌剂组合的化合物将在培养物和小鼠中进行测试，耐药C.白色念珠菌和C.新人类除了产生重要的基本见解，我们的结果是在不久的将来，可能会通过提供有希望的线索来影响侵袭性真菌感染的治疗。开发以新方式运作的实际抗真菌候选药物。