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.

摘要/摘要病原微生物的内在耐药性和获得性耐药性对人类健康构成严重威胁真菌病原体在全球范围内造成了巨大的经济后果，这是一个特殊的挑战。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。最成问题的真菌病原体是隐球菌属，每年导致超过 180,000 人死亡在全球范围内，隐球菌性脑膜炎是该病的主要临床表现，死亡率为 100%。如果不及时治疗，即使采用最好的治疗方法，死亡率仍然很高，因为药物的数量太多。在真菌中具有不同靶标的类别非常有限，并且当前抗真菌药物的用途是有限的。受到剂量限制性宿主毒性或频繁出现的新的非耐药性的影响。迫切需要治疗干预的交叉反应目标。在 NIAID 先前支持下进行的工作中，我们已经证明，针对分子伴侣 Hsp90 隐球菌和其他真菌中的抗真菌药物提供了增强抗真菌药物功效的强大策略 Hsp90 的“成药性”已被许多小分子证实。目前该蛋白的抗真菌活性和毒性较差。然而，需要按照本修订版中的建议开发真菌选择性抑制剂重新提交。为了追求真菌选择性的目标，我们的跨学科团队现已解决了药物的结构- 白色念珠菌和新型隐球菌 Hsp90 的结合域（未结合和抑制剂结合）这些化学结构研究确定了构象灵活性的真菌特异性差异。使我们能够设计、合成和表征新化学类别的真菌选择性抑制剂。利用我们用之前的资金开发的新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（Cowen）以及药物化学方面的互补专业知识（布朗）继续进行结构活动关系（SAR）研究，但现在增加了新的研究开发了计算算法来生成具有广谱抗真菌活性的抑制剂。单独的化合物以及与标准抗真菌药物的组合将在培养物和小鼠体内进行测试除了产生重要的基本见解外，我们的结果还包括耐药白色念珠菌和新型念珠菌。通过提供有希望的线索，可能会在不久的将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。