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

描述(申请人提供)：隐球菌性脑膜炎(CM)仍然是艾滋病毒阳性患者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世界性健康问题。北美艾滋病毒感染者的死亡率估计为20%，尽管他们可以获得良好的医疗保健。在撒哈拉以南非洲，估计每年有530,000名艾滋病毒阳性患者死于CM，而普通人群中的结核病死亡人数为350,000。几十年来，两性霉素B(Amb)一直是CM的主要治疗药物。然而，它往往无法治愈或根除隐球菌感染。AMB会导致严重的毒性，包括肾毒性和白细胞减少症，口服制剂中没有这种药物。在这项提案中，我们计划使用真菌钙调神经磷酸酶的同源建模和新开发的化学来发现一种口服、耐受性好、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。这种新的治疗方法将有可能作为单一药物使用，或与AMB或口服三氮唑联合使用，以提高存活率和对治疗方案的依从性。我们的目标是：1.对新型隐球菌钙调神经磷酸酶/FKBP12/FK506三元复合体进行计算机模拟，设计出新型隐球菌钙调神经磷酸酶的无毒小分子抑制剂。2.使用收敛的方法合成第一代30种非免疫抑制真菌钙调神经磷酸酶抑制剂文库；连续几代文库将由Aim 3.3的经验数据指导。3.筛选和选择化合物对新生弧菌菌株和新兴隐球菌种的抗真菌活性，PK/PD性质，并基于观察到的SAR迭代文库。 公共卫生相关性：隐球菌性脑膜炎(CM)仍然是艾滋病毒阳性者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死亡率高达70%的一个主要的世界性健康问题。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建议创造一类新的抗真菌药物，对隐球菌具有杀菌活性，这将简化和缩短治疗方案的持续时间，并降低因隐球菌病而导致的死亡率。

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.