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（例如，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，但主要制药公司基本上忽视了这一点。对于生活在高感染率地区的许多人来说，治疗热带疾病的费用通常高得令人望而却步。此外，许多热带疾病正在对现有的治疗产生抗药性，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，具有通过合成或组合化学不易获得的独特特性。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多样性化合物，其中一些将抑制热带疾病的感染和/或传播。这些来自海洋蓝细菌的新活性化合物与现有药剂相比还可以提供增加的功效、克服抗性的能力和/或减少的副作用，因此可能适合于未来的临床前和临床开发。总部设在巴拿马的国际生物多样性合作小组（ICBG）题为“巴拿马药物定向发现”，参与了一项为期九年的努力，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，以继续寻找更好、更便宜的热带疾病治疗方法。因此，提出了以下具体目标：SA 1，采用生态学指导的海洋采集技术采集标本进行筛选; SA 2，提取海洋标本，进行提取物的预分级，并送去筛选对包括疟疾、恰加斯病和利什曼病在内的热带疾病的体外活性，以及细胞毒性试验-根据生物测定结果对馏分进行优先级排序，以进行进一步分析：在一个测定中表现出有效活性而对其它测定影响最小且具有相应低细胞毒性的级分将继续进行进一步分离和化合物分离; SA 3，进行生物测定指导的分离，以分离和鉴定对这些热带疾病起作用的化合物。这些具体目标为国际研究科学家发展奖（IRSDA）提供了重点，涉及美国和外国导师，他们在巴拿马ICBG上合作多年，并为候选人的培训和指导制定了巨大的计划。

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.