A Structural Approach for Treating Drug Resistant Fungal Pathogens

治疗耐药真菌病原体的结构方法

• 批准号: 8315147
• 负责人: MITCHELL W MUTZ
• 金额: $ 25.81万
• 依托单位: AMPLYX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8315147
• 关键词: Amino Acid Sequence; Antifungal Agents; Aspergillosis; Aspergillus; Binding; Calcineurin; Calcineurin Pathway; Calcineurin inhibitor; Candida; Candida albicans; Caspofungin; Cause of Death; Combined Modality Therapy; Complement; Complex; Cryptococcus; Crystallization; Cyclic Peptides; Cyclophilin A; Cyclosporine; Disease; Disseminated candidiasis; Drug Delivery Systems; Drug resistance; Escherichia coli; Fluconazole; Fungal Drug Resistance; Fungal Proteins; Goals; Growth; Homology Modeling; Human; Immune System Diseases; Immunocompromised Host; Immunosuppression; Immunosuppressive Agents; In Vitro; Industrial fungicide; Infection; Lead; Length; Libraries; Ligands; Malignant Neoplasms; Methods; Minimum Inhibitory Concentration measurement; Modeling; Molecular Models; Mycoses; Nosocomial Infections; Organ Transplantation; Patients; Peptide Library; Pharmaceutical Preparations; Proteins; Protons; Publishing; Regimen; Resistance; Resolution; Roentgen Rays; Structure; Structure-Activity Relationship; Testing; Therapeutic; Toxic effect; Transplant Recipients; Triazoles; United States; analog; base; biological adaptation to stress; cost; design; fenpropimorph; fungus; in vivo; inhibitor/antagonist; insight; molecular modeling; mortality; pathogen; protein expression; protein structure; resistant strain; small molecule; therapeutic target; tool

DESCRIPTION (provided by applicant): There is an urgent need to discover more effective therapeutic regimens for fungal infections. Nosocomial infections caused by Candida albicans have a 50% mortality rate. Aspergillosis is a leading cause of death in organ transplant recipients, as well as patients suffering from cancer and auto-immune disorders. The annual cost of treating fungal infections is about $2.6 billion in the United States and is increasing due to the larger number of immunocompromised patients who suffer from these illnesses. The emergence of fungal drug resistance to widely used antifungals including triazoles and echinocandins further compromises the efficacy of the limited armamentarium of antifungal therapeutics. A number of in vitro and in vivo studies have established that molecules which inhibit the fungal protein, calcineurin, are highly synergistic with several important classes of antifungal therapeutics including triazoles and echinocandins. However, a great challenge with exploiting fungal calcineurin as a therapeutic target is the structural similarity to human calcineurin, and that inhibition of human calcineurin causes severe immunosuppression and toxicity. By solving the X-ray crystal structure of calcineurin from C. albicans, we hope to gain insight into the structure activity relationships of non- immunosuppressive cyclosporin A analogues. We hope to develop these cyclosporin A analogues as potent antifungals employing the following steps: 1. Homology model the known x-ray crystal structure of the ternary complex of H. sapiens calcineurin/cyclosporin A/cyclophilin A to create a model of the ternary structure of C. albicans calcineurin/cyclopsorin A/cyclophilin A. 2. Determine the x-ray crystal structure of the ternary complex of C. albicans calcineurin, cyclosporin A, cyclophilin A. 3. Design and synthesize cyclosporin A analogues by comparing the human ternary structure with the fungal ternary structures generated by the homology model and/or x-ray model and employing molecular modeling tools to assist with library design. 4. Screen and select compounds against both C. albicans and non-albicans Candida strains. PUBLIC HEALTH RELEVANCE: Fungal infections represent a significant challenge due to the limited armamentarium available to treat diseases caused by fungi. Nosocomial infections caused by Candida albicans have a 50% mortality rate. Amplyx proposes a new combination therapy approach to treating drug resistant fungal infections via the design and synthesis of non-immunosuppressive molecules to inhibit fungal calcineurin that can be co- administered with existing antifungals.

描述(由申请人提供)：迫切需要找到更有效的真菌感染治疗方案。由白色念珠菌引起的医院感染的死亡率为50%。曲霉病是器官移植受者以及患有癌症和自身免疫性疾病的患者的主要死亡原因。在美国，每年治疗真菌感染的费用约为26亿美元，而且还在增加 更多患有这些疾病的免疫功能低下的患者。真菌对包括三氮唑和棘球菌素在内的广泛使用的抗真菌药物的耐药性的出现，进一步损害了有限的抗真菌治疗药物的疗效。许多体外和体内研究已经证实，抑制真菌蛋白钙调神经磷酸酶的分子与几类重要的抗真菌药物具有高度的协同作用，包括三氮唑和棘球菌素。然而，利用真菌钙调神经磷酸酶作为治疗靶点的一个巨大挑战是结构上与人钙调神经磷酸酶相似，而且抑制人钙调神经磷酸酶会导致严重的免疫抑制和毒性。通过解析白念珠菌钙调神经磷酸酶的X射线晶体结构，我们希望能够深入了解非免疫抑制环孢素A类似物的构效关系。我们希望通过以下步骤开发这些环孢菌素A类似物作为有效的抗真菌药物：1.对已知的智慧型钙调神经磷酸酶/环孢菌素A/亲环素A三元络合物的X射线晶体结构进行同源建模，以创建一个三元结构的模型 白念珠菌钙调神经磷酸酶/环孢素A/亲环素A三元复合体的X射线晶体结构测定3.将人的三元结构与同源模型和/或X射线模型生成的真菌三元结构进行比较，并利用分子模拟工具辅助文库设计。4.筛选抗白色念珠菌和非白色念珠菌的化合物。 公共卫生相关性：真菌感染是一个重大挑战，因为可用于治疗由真菌引起的疾病的医疗设备有限。由白色念珠菌引起的医院感染的死亡率为50%。Amplyx提出了一种新的联合治疗方法，通过设计和合成非免疫抑制分子来抑制真菌钙调神经磷酸酶，从而与现有的抗真菌药物联合使用，从而治疗耐药真菌感染。