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

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世界性健康问题。在北美，尽管获得了良好的医疗保健，但艾滋病毒感染者的死亡率估计为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53万人死亡，而在一般人群中，结核病每年造成35万人死亡。几十年来，两性霉素B （AmB）一直是治疗CM的主要药物。然而，它往往不能治愈或根除隐球菌感染。AmB引起严重的毒性，包括肾毒性和白细胞减少症，并且不能用于口服制剂。在本研究中，我们计划利用真菌钙调磷酸酶的同源性建模和新发展的化学发现一种口服、耐受性好、低毒的杀真菌药物用于治疗CM。人类和真菌蛋白之间的氨基酸序列变化将被用来修饰免疫抑制分子FK506和ascomycin，以创造一种无毒的新的化学实体，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；对新隐球菌钙调磷酸酶/FKBP12/FK506三元配合物进行计算建模，设计新隐球菌钙调磷酸酶的无毒小分子抑制剂。2. 采用收敛法合成第一代30种非免疫抑制真菌钙调磷酸酶抑制剂文库接下来的几代人将以Aim 3的经验数据为指导。3. 筛选和选择化合物对新生隐球菌和新出现的隐球菌的抗真菌活性，pk/pd性质，并根据观察到的SAR迭代文库。

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. 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.