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

描述（由申请人提供）：隐球菌脑膜炎（CM）仍然是HIV阳性个体死亡的重要原因，也是包括非洲和东南亚在内的发展中地区的主要全球健康问题。在北美，尽管可以获得良好的医疗保健，但艾滋病毒感染者的估计死亡率为20%。在撒哈拉以南非洲，CM每年在艾滋病毒阳性患者中造成约530，000人死亡，而在普通人群中造成350，000人死亡。几十年来，两性霉素B（AmB）一直是CM的主要治疗药物。然而，它往往不能治愈或根除隐球菌感染。AmB会导致严重毒性，包括肾毒性和白细胞减少症，并且无法以口服制剂形式提供。在这个提议中，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方法来发现一种口服的、耐受性良好的、毒性低的杀真菌药物，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FK 506和子囊霉素，以产生一种无毒的新化学实体，靶向真菌钙调磷酸酶。这种新的治疗方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/FKBP 12/FK 506的三元复合物进行计算建模，以设计无毒的小分子C.新生动物钙调神经磷酸酶2.使用收敛方法合成30种非免疫抑制性真菌钙调磷酸酶抑制剂的第一代文库;后续世代将由目标3的经验数据指导。3.筛选和选择抗念珠菌菌株的抗真菌活性化合物。新型隐球菌和新出现的隐球菌物种、pk/pd特性和基于观察到的SAR的pcr文库。

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.