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）：迫切需要发现更有效的真菌感染治疗方案。白色念珠菌引起的医院感染死亡率为 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死亡的主要原因。在美国，每年治疗真菌感染的费用约为 26 亿美元，并且由于以下因素而不断增加： 为大量患有这些疾病的免疫功能低下的患者提供帮助。真菌对广泛使用的抗真菌药物（包括三唑和棘白菌素）产生耐药性的出现进一步损害了有限的抗真菌治疗药物的功效。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包括三唑和棘白菌素在内的几类重要的抗真菌治疗药物具有高度协同作用。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其与人钙调神经磷酸酶的结构相似性，并且抑制人钙调神经磷酸酶会导致严重的免疫抑制和毒性。通过解析来自白色念珠菌的钙调神经磷酸酶的X射线晶体结构，我们希望深入了解非免疫抑制性环孢菌素A类似物的结构活性关系。我们希望通过以下步骤将这些环孢菌素 A 类似物开发为有效的抗真菌剂： 1. 对智人钙调神经磷酸酶/环孢菌素 A/亲环菌素 A 三元复合物的已知 X 射线晶体结构进行同源模型，以创建 C. albicans calcineurin/cyclopsorin A/cyclophilin A。 2. 确定 C. albicans calcineurin、cyclosporin A、cyclophilin A 三元复合物的 X 射线晶体结构。 3. 通过将人类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，并采用分子设计和合成环孢菌素 A 类似物 协助库设计的建模工具。 4. 筛选并选择针对白色念珠菌和非白色念珠菌菌株的化合物。