Tropical Disease Drug Discovery from Marine Cyanobacteria in Panama

描述（由申请人提供）：热带寄生虫病和传染病（如疟疾、南美锥虫病、利什曼病和登革热）对全球健康构成巨大威胁，但在很大程度上被主要制药公司所忽视。对于生活在高感染率地区的许多人来说，热带病的治疗费用通常高得令人望而却步。此外，许多热带病正在对现有的治疗方法产生耐药性，或者没有有效的治疗方法。天然产物含有高度多样化的结构，具有独特的特征，不易通过合成或组合化学获得。这项研究的假设是，来自巴拿马生物多样性海洋的海洋物种将产生化学上多样化的化合物，其中一些化合物将抑制热带疾病的感染和/或传播。与现有药物相比，这些来自海洋蓝藻的新活性化合物还可能提供更高的功效，克服耐药性的能力和/或减少副作用，因此可能适合未来的临床前和临床开发。设在巴拿马的国际生物多样性合作小组（ICBG）题为“巴拿马生态导向药物发现”，参与了一项为期9年的努力，致力于确定疟疾、恰加斯病、利什曼病和癌症的治疗方法。需要收集新的海洋标本，以继续寻找治疗热带病的改进的、更便宜的治疗方法。为此，提出了以下具体目标：1、利用生态引导海洋采集技术采集标本进行筛选；SA 2，提取海洋标本，对提取物进行预分离，并送去筛选抗热带疾病（包括疟疾、恰加斯病和利什曼病）的体外活性，以及进行细胞毒性测试——根据生物测定结果优先考虑进行进一步分析的馏分：在一种测定中表现出强大活性，对其他测定影响最小且具有相应低细胞毒性的馏分将继续进行进一步分离和化合物分离；sa3，进行生物测定引导分离，以分离和鉴定对这些热带病起作用的化合物。这些具体目标为国际研究科学家发展奖（IRSDA）提供了重点，该奖项涉及在巴拿马ICBG上合作多年的美国和外国导师，他们为候选人的培训和指导制定了一个庞大的计划。

DESCRIPTION (provided by applicant): Tropical parasitic and infectious diseases (e.g., malaria, Chagas' disease, leishmaniasis, and Dengue fever) pose enormous global health threats, but are largely ignored by the major pharmaceutical companies. Treatments for tropical diseases are generally prohibitively expensive for many people living in areas of high rates of infection. Furthermore, many tropical diseases are developing resistance to currently available treatments, or are without effective treatments. Natural products contain highly diverse structures with unique characteristics not readily accessible through synthetic or combinatorial chemistry. The hypothesis for this research is that marine species from the biologically diverse oceans in Panama will yield chemically diverse compounds, some of which will inhibit the infection and/or spread of tropical diseases. These new active compounds from marine cyanobacteria may also provide increased efficacy, ability to overcome resistance, and/or reduced side effects as compared with existing agents, and thus could be appropriate for future preclinical and clinical development. The International Cooperative Biodiversity Group (ICBG) based in Panama entitled "Ecologically Directed Drug Discovery in Panama" has been involved in a nine year effort, working to identify treatments for malaria, Chagas' disease, leishmaniasis, and cancer. New collections of marine specimens are needed to continue the search for improved, less expensive treatments for tropical diseases. Thus, the following specific aims (SA) are proposed: SA 1, use ecologically guided marine collection techniques to collect specimens for screening; SA 2, extract marine specimens, perform pre-fractionation of extracts, and send for screening for in vitro activity against tropical diseases including malaria, Chagas' disease, and leishmaniasis, as well as for cytotoxicity testing - prioritize fractions for further analysis based on bioassay results: fractions that exhibit potent activity in one assay with minimal effect on other assays and with corresponding low cytotoxicity will continue on for further fractionation and compound isolation; SA 3, conduct bioassay-guided fractionation to isolate and identify compounds that act against these tropical diseases. These specific aims provide the focus for this International Research Scientist Development Award (IRSDA), involving U.S. and foreign mentors who have collaborated for years on the Panama ICBG, and who have in place a tremendous plan for the training and mentorship of the candidate.