New Antimalarials from Plant-Pathogenic Fungi

来自植物病原真菌的新型抗疟药

• 批准号: 6812699
• 负责人: NP D NANAYAKKARA
• 金额: $ 21.19万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6812699
• 关键词: Plasmodium falciparum; antimalarial agents; bioassay; biological products; drug discovery /isolation; drug resistance; drug screening /evaluation; herbicides; laboratory mouse; malaria; microorganism metabolism; mycotoxins; pharmacokinetics; tissue /cell culture

DESCRIPTION (provided by the applicant): Plasmodium falciparum, which often causes fatal cerebral malaria, especially among children, has developed resistance to the one very effective antimalarial drug chloroquine and is developing resistance to other antimalarial drugs introduced more recently such as mefloquine and halofantrin. Therefore, there is an urgent need to develop alternative drugs to counter this trend. Natural products isolated from higher plants, such as quinine and artemisinin, have provided effective drugs against malaria. In the last few decades a large number of plants, including those traditionally used, have been evaluated for their antimalarial activity. However, no new drug candidates and very few lead compounds have emerged from these efforts. Because of the ease of rapid mass production and good chemical diversity, fungi remain a good and attractive natural source for biologically active compounds. Fungi have provided the majority of agents and lead compounds currently used against bacterial infections. A few of these antibiotics are effective in combination with conventional antimalarial drugs against drug-resistant falciparum malaria. However, only very few extracts or secondary metabolites of fungi have been systematically evaluated for their antimalarial activity. Plant pathogenic fungi are known to release phytotoxic secondary metabolites, which disrupt biochemical processes in plant cells. Genomic and recent biochemical studies have shown that there are a number of plant-like metabolic pathways in the malaria parasite. Our preliminary results indicate that plant pathogenic fungi can be a good source of antimalarial compounds. The purpose of this proposal is to expand on these results and to identify antimalarial compounds from plant pathogenic fungi and their preliminary evaluation as new clinically useful antimalarial agents.

描述(由申请人提供)：恶性疟原虫经常导致致命的脑型疟疾，特别是在儿童中，它对一种非常有效的抗疟疾药物氯喹产生了抗药性，并对最近引入的其他抗疟疾药物，如甲氟喹和氟喹啉产生了抗药性。因此，迫切需要开发替代药物来对抗这一趋势。 从高等植物中分离出来的天然产物，如奎宁和青蒿素，提供了有效的抗疟疾药物。在过去的几十年里，大量的植物，包括那些传统上使用的植物，已经被评估了它们的抗疟疾活性。然而，从这些努力中没有出现新的候选药物，也没有出现很少的先导化合物。由于易于快速大规模生产和良好的化学多样性，真菌仍然是具有生物活性的化合物的良好和有吸引力的天然来源。真菌提供了目前用于治疗细菌感染的大多数制剂和先导化合物。其中几种抗生素与传统的抗疟疾药物联合使用对抗药性恶性疟疾有效。然而，只有极少数的真菌提取物或次生代谢物被系统地评价其抗疟疾活性。 植物病原真菌能释放植物毒性次生代谢产物，扰乱植物细胞的生化过程。基因组和最近的生化研究表明，疟疾寄生虫中有许多类似植物的代谢途径。我们的初步结果表明，植物病原真菌可以作为抗疟疾化合物的良好来源。这项建议的目的是扩大这些结果，并从植物病原真菌中鉴定抗疟疾化合物，并对其作为新的临床有用的抗疟疾药物进行初步评价。