A Computer Modeling Approach to Create an Antifungal to Improve the Treatment of

一种计算机建模方法来创建抗真菌药物以改善治疗

• 批准号: 8411022
• 负责人: MITCHELL W MUTZ
• 金额: $ 35万
• 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: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8411022
• 关键词: Acute; Adverse effects; Africa; Africa South of the Sahara; AmBisome; Amino Acid Sequence; Amphotericin B; Antifungal Agents; Arrhythmia; Binding; Calcineurin; Calcineurin inhibitor; Cessation of life; Chemicals; Chemistry; Clinical; Complex; Computer Simulation; Cryptococcal Meningitis; Cryptococcus; Cryptococcus neoformans infection; Cytochrome P450; Data; Disease; Drug Formulations; Exhibits; FDA approved; FK506; Fluconazole; Flucytosine; Fungal Proteins; General Population; Generations; Generic Drugs; Goals; HIV; HIV Seropositivity; Headache; Health; Healthcare; Homology Modeling; Human; Immunosuppression; Immunosuppressive Agents; In Vitro; Incidence; Individual; Industrial fungicide; Infection; Intracranial Hypertension; Leukopenia; Libraries; Lipids; Liposomes; Maintenance Therapy; Membrane; Metabolism; Methods; Nausea and Vomiting; Neoadjuvant Therapy; North America; Oral; P-Glycoprotein; Patients; Permeability; Pharmaceutical Preparations; Property; Proteins; Resistance; Resources; Roentgen Rays; Sales; Screening procedure; Southeastern Asia; Structure; Survival Rate; Symptoms; Tacrolimus Binding Protein 1A; Tacrolimus Binding Proteins; Therapeutic; Time; Toxic effect; Treatment Protocols; Treatment outcome; Triazoles; Tuberculosis; Work; Yeasts; analog; ascomycin; base; biological adaptation to stress; combat; compliance behavior; cost effective; counterscreen; design; improved; in vivo; inhibitor/antagonist; mortality; nephrotoxicity; novel therapeutics; small molecule; small molecule libraries; theories

DESCRIPTION (provided by applicant): Cryptococcal meningitis (CM) continues to be a significant cause of mortality among HIV positive individuals, and a major world-wide health concern in developing regions including Africa and Southeast Asia. The estimated mortality rate is 20% for infected HIV positive individuals in North America, despite access to good healthcare. In sub-Saharan Africa, CM causes an estimated 530,000 deaths per year among HIV positive patients compared with 350,000 for tuberculosis in the general population. For decades, Amphotericin B (AmB) has been the mainstay therapeutic for CM. However, it often fails to cure or eradicate cryptococcal infections. AmB causes severe toxicities including nephrotoxicity and leukopenia, and is not available in an oral formulation. In this proposal, we plan to use homology modeling of fungal calcineurin and newly developed chemistry to discover an oral, well tolerated fungicidal drug with low toxicity to use in the treatment of CM. Amino acid sequence changes between human and fungal proteins will be exploited to modify the immunosuppressive molecules FK506 and ascomycin to create a non-toxic, new chemical entity that targets fungal calcineurin. This new therapeutic will have the potential to be employed as a single agent or in combination with AmB or orally available triazoles to improve survival rates and compliance with treatment regimens. Our Aims are: 1. Perform computational modeling of the ternary complex of Cryptococcal neoformans calcineurin/FKBP12/FK506 to design non-toxic small molecule inhibitors of C. neoformans calcineurin. 2. Synthesize a first generation library of 30 non-immunosuppressive fungal calcineurin inhibitors using a convergent approach; successive generations will be guided by empirical data from Aim 3. 3. Screen and select compounds for antifungal activity against strains of C. neoformans and emerging cryptococcal species, pk/pd properties, and iterate library based on observed SAR. PUBLIC HEALTH RELEVANCE: Cryptococcal meningitis (CM) continues to be a significant cause of mortality among HIV positive individuals, and a major world-wide health concern in developing regions including Africa and Southeast Asia where mortality rates reach 70%. There is a clear need for new, cost effective therapeutics which will enable patient compliance with treatment regimens. Amplyx proposes to create a new class of antifungal drugs with fungicidal activity against Cryptococcus which will simplify and reduce the duration of treatment regimens, and lower the mortality rates due to cryptococcosis.

描述（由申请人提供）：隐球菌脑膜炎（CM）仍然是艾滋病毒阳性个体死亡的重要原因，以及在包括非洲和东南亚在内的发展地区的全球健康关注。尽管获得了良好的医疗保健，但北美感染的艾滋病毒阳性个体的估计死亡率为20％。在撒哈拉以南非洲，艾滋病毒阳性患者的CM估计每年死亡530,000例，而总人群的结核病为350,000例。几十年来，两性霉素B（AMB）一直是CM的主要治疗方法。但是，它通常无法治愈或根除隐球菌感染。 AMB会引起严重的毒性，包括肾毒性和白细胞减少症，并且在口服配方中不可用。在此提案中，我们计划使用真菌钙调蛋白和新开发的化学的同源性建模，以发现一种口服，耐受性良好的杀真菌药物，毒性低，用于治疗CM。人与真菌蛋白之间的氨基酸序列变化将被利用，以修饰免疫抑制分子FK506和Ascomycin，以创建靶向真菌钙调蛋白的无毒的新化学实体。这种新的治疗方法有可能被用作单一药物，或与AMB或口服三唑结合使用，以提高生存率并遵守治疗方案。我们的目的是：1。对加密秒新生虫的三元复合物进行计算建模，以设计新外形钙调蛋白钙化蛋白的无毒小分子抑制剂。 2。使用收敛近的方法合成了30个非免疫抑制真菌钙调神经蛋白抑制剂的第一代文库；后代将以AIM3。3的经验数据为指导。筛选和选择化合物，用于针对新生梭菌的菌株和新兴的加密秒性，PK/PD特性以及基于观察到的SAR的迭代库。 公共卫生相关性：隐球菌脑膜炎（CM）仍然是艾滋病毒阳性个体死亡的重要原因，以及在包括非洲和东南亚在内的发展地区，死亡率达到70％的发展地区的主要健康关注。显然需要新的，具有成本效益的治疗剂，这将使患者遵守治疗方案。 Amplyx提议创建一种针对隐孢子虫的杀真菌活性的新型抗真菌药物，这将简化并减少治疗方案的持续时间，并降低由于隐孢子虫病而导致的死亡率。