| 李鹏杰,曹西珍,顾玉诚,等.海洋天然药物研究进展系列一：海洋天然产物在抗疟药物研发中的挑战与机遇[J].中国海洋药物,2025,(2):-. |
| 海洋天然药物研究进展系列一：海洋天然产物在抗疟药物研发中的挑战与机遇 |
| Research Progress in Marine Natural Products I: challenges and opportunities of marine natural products in the research and development of antimalarial drugs |
| 投稿时间：2025-01-15 修订日期：2025-03-12 |
| DOI： |
| 中文关键词: 疟疾、海洋天然产物、耐药性、抗疟药物、作用靶标与机制 |
| English Keywords:malaria, marine natural products, drug resistance, target and mechanism of action |
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| 中文摘要: |
| 疟疾是一种由雌性按蚊传播引起的原生动物寄生虫性疾病，是由疟原虫引起的最致命的人类寄生虫感染疾病之一。据世界卫生组织全球疟疾报告显示，全球超过84个国家受疟疾影响，严重威胁着人类的健康。自2000年以来，疟疾感染人数常年维持在2.5亿左右，每年约有60万人死于疟疾。目前疟原虫对青蒿素在内的大部分市售药物产生广泛的耐药性，并在部分国家出现青蒿素联合治疗法（ACT）的多药耐药问题。虽然近年来上市了多款以预防性为主的疟疾疫苗，但在治疗药物方面，自2020年后尚无新型药物上市。随着耐药问题的不断恶化，若无新型药物的出现，疟疾对人类的威胁将进一步加重。因此，研发高效、低毒的新型抗疟药物迫在眉睫。海洋复杂的环境使得海洋生物进化出不同于陆地生物的特殊代谢途径，从而产生大量结构新颖、活性显著的活性天然产物，为创新药物研发提供了重要的资源宝库。在海洋丰富的生物资源中，海绵、刺胞动物、藻类、棘皮动物以及红树等是海洋天然产物的传统来源，但自2002年起，海洋微生物，尤其是海洋真菌逐步成为新海洋天然产物的最大来源。在新型抗疟药物的研发中，海洋天然产物也展现出巨大的发展潜力，近三十年来，大批具有显著活性的抗疟先导分子被发现，其中，新型大环内酯类化合物bastimolide A、聚酮类化合物trioxacarcin A、trioxacarcin D以及生物碱类化合物manzamine A、(+)-8-hydroxymanzamine A等化合物抗疟活性均达到了纳摩尔级，具有深入研究的价值。此外，对海洋抗疟天然产物作用靶点/作用机制的研究也开始逐步推进，并取得了实效进展。如，作用于蛋白质法呢基转移酶的alisiaquinones A–C、抑制疟原虫血红蛋白聚合，降低线粒体膜电位以及抑制恶性疟原虫DNA旋转酶的多靶点抑制剂monocerin-1n以及作用于恶性疟原虫单酰基甘油脂酶样蛋白(PfMAGLLP)的salinipostins A等均具有不同于现有抗疟药物的作用靶标/机制，是未来开发新型抗疟药物的重要先导分子。然而，海洋创新药物研发也面临诸多挑战，如生物样品采集困难、天然活性成分含量低微、天然化合物重复发现、作用机制不清等。随着技术的发展，越来越多的新兴技术应用于海洋天然产物的发现与后续研究中去：如基于基因组挖掘技术与分子网络技术的新型天然产物高效发现，基于生物合成与化学合成的微量天然产物规模制备以及基于多组学技术的活性化合物作用靶标与机制研究等。海洋天然产物优异的抗疟活性、研究技术的发展与革新将极大推动抗疟海洋药物的发展，开发“海洋来源的青蒿素”或许将不再是梦想。 |
| English Summary: |
| Malaria is a protozoan parasitic disease transmitted by female anopheles mosquitoes, and it is one of the most deadly human parasitic infections caused by Plasmodium parasites. According to the World Health Organization's Global Malaria Report, more than 84 countries are affected by malaria. Since 2000, the number of people infected with malaria has remained at around 250 million annually, and there are about 600,000 deaths from malaria every year, which poses a serious threat to human health. At present, Plasmodium species has developed extensive resistance to most commercially available drugs including artemisinin. In some countries, there is a problem of multi-drug resistance in the combination therapy with artemisinin (ACT). Although several preventive malaria vaccines have been launched in recent years, there has been no new drug on the market since 2020. With the continuous deterioration of drug resistance, if there are no new drugs available, malaria will face a situation where there are no drugs to use. Therefore, it is urgent to develop highly effective and low-toxic new anti-malarial drugs. The complex marine environment makes marine organism special metabolic pathways that are different from terrestrial organisms, which results in a large number of active natural products with novel structure and significant activity and provides an important resource treasure house for innovative drug research and development. Among the rich marine biological resources, sponges, cnidarians, algae, echinoderms and mangroves are the traditional sources of marine natural products, but since 2002, marine microorganisms, especially marine fungi, have gradually become the largest source of new marine natural products. In the research and development of new antimalarial drugs, marine natural products also show great development potential. In the past three decades, a large number of anti-malaria leading molecules with significant activity have been found. Among them, bastimolide A (macrolide compounds), trioxacarcin A, trioxacarcin D (polyketides), manzamine A and (+)-8-hydroxymanzamine A (alkaloids) all exhibit nanomolar levels of antimalarial activity, making them worthy of further study. In addition, the research on marine anti-malarial natural products' target/mechanism of action has gradually advanced and has achieved practical progress in recent years. A lot of marine natural products have different targets/mechanisms from existing drugs, such as monocerin-1n (multi-target inhibitors that inhibit the aggregation of Plasmodium hemoglobin, reduce mitochondrial membrane potential and inhibit DNA gyrase of Plasmodium falciparum), alisiaquinones A–C (protein farnesyltransferase inhibitors) and salinipostin A (plasmodial monoacylglycerol lipase-like protein (PfMAGLLP) inhibitor), which are important resources for developing new anti-malarial lead molecules in the future. However, the research and development of innovative marine drugs also face many challenges, such as difficulty in collecting biological samples, low content of natural active ingredients, repeated discovery of natural compounds, unclear mechanism of action, etc. With the development of technology, more and more emerging technologies are applied to the discovery and follow-up research of marine natural products, such as the efficient discovery of new natural products based on genome mining technology and molecular network technology, the regular preparation of trace natural products based on biosynthesis and chemical synthesis, and the target and mechanism research of active compounds based on multigroup technology. The excellent antimalarial activity of marine natural products, along with the development and innovation of research techniques will greatly promote the development of antimalarial marine drugs. Developing “artemisinin from marine sources” may no longer be a dream. |
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