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: 8497619
• 负责人: MITCHELL W MUTZ
• 金额: $ 30万
• 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/8497619
• 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 Targeting; 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.

描述（由申请人提供）：迫切需要发现对真菌感染的更有效的治疗方案。由白色念珠菌引起的医院感染具有50％的死亡率。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死亡的主要原因。在美国，治疗真菌感染的年度费用约为26亿美元 对于患有这些疾病的人数大量的免疫功能低下的患者。真菌耐药性耐药性对包括三唑和棘齿毒素在内的广泛使用的抗真菌抗体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确定，抑制真菌蛋白钙调蛋白的分子与包括三唑和echinocantins在内的几类重要类别的抗真菌疗法相协同。然而，将真菌钙调神经蛋白酶作为治疗靶靶标的巨大挑战是与人钙调蛋白的结构相似性，并且抑制人钙调蛋白会导致严重的免疫抑制和毒性。通过求解来自白色念珠菌的钙调蛋白的X射线晶体结构，我们希望深入了解非免疫抑制环孢菌素A类似物的结构活性关系。我们希望开发这些环孢素A类似物作为使用以下步骤的有效抗真菌剂：1。同源性模型H. sapiens钙调蛋白/环孢菌素A/环孢菌素A的已知X射线晶体结构已知的X射线晶体结构，以创建一个模型 C. albicans钙调蛋白/环虫蛋白A/环蛋白A. 2。确定白色念珠菌钙调蛋白，环孢菌素A，环胞蛋白A的X射线晶体结构A，环蛋白A。3。设计和合成环孢子蛋白与人类特尔尼结构或使用Fungal Ternary Trienter-ternary Troduly Alogial-Ternary Troduly Alogient a cyclosporin a，并通过使用Fungal Ternary Tornary Troduly-ternary Tologuility-ternary Tologiel copentir ternary Tologial-ternary Tologial-ternary Tologial-ternary结构建模工具以协助图书馆设计。 4。针对白色念珠菌和非阿尔比克念珠菌菌株的筛网和选择化合物。