Antifungal sphingolipids for AIDS-related Mycoses

抗真菌鞘脂治疗艾滋病相关真菌病

• 批准号: 6655355
• 负责人: Tadeusz F Molinski
• 金额: $ 3.8万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6655355
• 关键词: AIDS; Candida; Commonwealth of Independent States; Cryptococcus neoformans; Porifera; antifungal agents; circular dichroism; drug discovery /isolation; drug screening /evaluation; fluconazole; high performance liquid chromatography; mass spectrometry; microorganism disease chemotherapy; mycosis; nuclear magnetic resonance spectroscopy; opportunistic infections; pharmacokinetics; sphingolipids; stereochemistry; thin layer chromatography

DESCRIPTION (provided by applicant): Russia has one of the highest rates of increase in new cases of AIDS in the developed world correlated with tumultuous social and economic upheaval in the past decade. The development of novel antifungal drugs with activity against AIDS-related opportunistic fungal disease, joined with regional efforts in drug discovery, is needed. Dimeric sphingolipids, which occur in marine sponges of restricted distribution, exhibit significant synergism in antifungal assays (in vitro) and may be useful leads in development of novel antimycotics with unique or complementary modes of action to clinical drugs. This AIDS-FIRCA proposal seeks to isolate and characterize novel dimeric sphingolipids from marine sponges of the family Leucettidae. New compounds will be isolated using solvent fractionation and chromatography and characterized using a variety of spectroscopic techniques, in particular mass spectrometry nuclear magnetic resonance spectroscopy (NMR) and circular dichroism (CD). Biological activity of pure antifungal compounds will be characterized using in vitro antifungal susceptibility testing in panel of fluconazole-resistant fungi. Lead compounds will be selected for advanced in vivo evaluation in murine models of fungemia.

描述（由申请人提供）： 俄罗斯是发达国家中艾滋病新发病例增长率最高的国家之一，这与过去十年社会和经济的动荡有关。需要开发具有抗艾滋病相关机会性真菌病活性的新型抗真菌药物，并结合区域药物发现的努力。二聚鞘脂存在于分布有限的海绵中，在抗真菌测定（体外）中表现出显着的协同作用，并且可能是开发具有独特或与临床药物互补作用模式的新型抗真菌药物的有用线索。该 AIDS-FIRCA 提案旨在从 Leucettidae 科海绵中分离和表征新型二聚鞘脂。新化合物将使用溶剂分馏和色谱法进行分离，并使用各种光谱技术进行表征，特别是质谱核磁共振波谱（NMR）和圆二色性（CD）。纯抗真菌化合物的生物活性将通过对氟康唑耐药真菌进行体外抗真菌药敏试验来表征。将选择先导化合物在真菌血症小鼠模型中进行高级体内评估。