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

基本信息

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
项目类别：
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

项目摘要

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）：隐球菌性脑膜炎（CM）仍然是艾滋病毒阳性个体死亡的一个重要原因，也是包括非洲和东南亚在内的发展中地区的一个主要的全球健康问题。尽管能够获得良好的医疗保健，但北美艾滋病毒阳性感染者的死亡率估计仍为 20%。在撒哈拉以南非洲地区，CM 每年导致 HIV 阳性患者死亡 530,000 人，而普通人群中的结核病死亡人数为 350,000 人。几十年来，两性霉素 B (AmB) 一直是 CM 的主要治疗方法。然而，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，并且不能以口服制剂形式提供。在本提案中，我们计划利用真菌钙调神经磷酸酶的同源模型和新开发的化学方法来发现一种口服、耐受性良好、毒性低的杀菌药物，用于治疗 CM。人类和真菌蛋白质之间的氨基酸序列变化将被用来修饰免疫抑制分子 FK506 和子囊霉素，以创建一种针对真菌钙调神经磷酸酶的无毒新化学实体。这种新疗法将有可能作为单一药物或与 AmB 或口服三唑类药物联合使用，以提高生存率和治疗方案的依从性。我们的目标是： 1. 对新型隐球菌钙调神经磷酸酶/FKBP12/FK506 三元复合物进行计算建模，设计新型隐球菌钙调神经磷酸酶的无毒小分子抑制剂。 2. 采用收敛方法合成第一代30种非免疫抑制性真菌钙调神经磷酸酶抑制剂文库；后代将受到目标 3 的经验数据的指导。 3. 筛选和选择对新型隐球菌菌株和新出现的隐球菌物种具有抗真菌活性的化合物、pk/pd 特性，并根据观察到的 SAR 迭代库。公共卫生相关性：隐球菌性脑膜炎 (CM) 仍然是 HIV 阳性个体死亡的一个重要原因，也是非洲和东南亚等发展中国家的一个主要全球健康问题，这些地区的死亡率高达 70%。显然需要新的、具有成本效益的治疗方法，使患者能够遵守治疗方案。 Amplyx 提议开发一类具有针对隐球菌杀菌活性的新型抗真菌药物，这将简化并缩短治疗方案的持续时间，并降低隐球菌病引起的死亡率。