Popruk Supaluk, Tummatorn Jumreang, Sreesai Suthasinee, Ampawong Sumate, Thiangtrongjit Tipparat, Tipthara Phornpimon, Tarning Joel, Thongsornkleeb Charnsak, Ruchirawat Somsak, Reamtong Onrapak
Department of Protozoology, Faculty of Tropical Medicine, Mahidol University, Ratchawithi Road, Ratchathewi, Bangkok, 10400, Thailand.
Program on Chemical Sciences, Chulabhorn Graduate Institute, Center of Excellence on Environmental Health and Toxicology (EHT), OPS, MHESI, 54 Kamphaeng Phet 6, Laksi, Bangkok, 10210, Thailand; Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok, 10210, Thailand.
Int J Parasitol Drugs Drug Resist. 2024 Dec;26:100561. doi: 10.1016/j.ijpddr.2024.100561. Epub 2024 Aug 13.
Giardia duodenalis, a widespread parasitic flagellate protozoan causing giardiasis, affects millions annually, particularly impacting children and travellers. With no effective vaccine available, treatment primarily relies on the oral administration of drugs targeting trophozoites in the small intestine. However, existing medications pose challenges due to side effects and drug resistance, necessitating the exploration of novel therapeutic options. Isocryptolepine, derived from Cryptolepis sanguinolenta, has demonstrated promising antimicrobial and anticancer properties. This study evaluated eighteen isocryptolepine-triazole adducts for their antigiardial activities and cytotoxicity, with ISO2 demonstrating potent antigiardial activity and minimal cytotoxicity on human intestinal cells. Metabolomics analysis revealed significant alterations in G. duodenalis metabolism upon ISO2 treatment, particularly affecting phospholipid metabolism. Notably, the upregulation of phytosphingosine and triglycerides, and downregulation of certain fatty acids, suggest a profound impact on membrane composition and integrity, potentially contributing to the parasite's demise. Pathway analysis highlighted glycerophospholipid metabolism, cytochrome b5 family heme/steroid binding domain, and P-type ATPase mechanisms as critical pathways affected by ISO2 treatment, underscoring its importance as a potential target for antigiardial therapy. These findings shed light on the mode of action of ISO2 against G. duodenalis and provide valuable insights for further drug development. Moreover, the study also offers a promising avenue for the exploration of isocryptolepine derivatives as novel therapeutic agents for giardiasis, addressing the urgent need for more effective and safer treatment options.
十二指肠贾第虫是一种广泛传播的寄生性鞭毛虫原生动物，可引起贾第虫病，每年影响数百万人，尤其对儿童和旅行者影响较大。由于没有有效的疫苗，治疗主要依赖于口服针对小肠内滋养体的药物。然而，现有药物因副作用和耐药性而面临挑战，因此有必要探索新的治疗选择。从红腺 cryptolepis 中提取的异隐品碱已显示出有前景的抗菌和抗癌特性。本研究评估了18种异隐品碱 - 三唑加合物的抗贾第虫活性和细胞毒性，其中ISO2表现出强大的抗贾第虫活性，对人肠道细胞的细胞毒性最小。代谢组学分析显示，ISO2处理后十二指肠贾第虫的代谢发生了显著变化，尤其影响磷脂代谢。值得注意的是，植物鞘氨醇和甘油三酯的上调以及某些脂肪酸的下调表明对膜组成和完整性有深远影响，这可能导致寄生虫死亡。通路分析强调甘油磷脂代谢、细胞色素b5家族血红素/类固醇结合结构域和P型ATP酶机制是受ISO2处理影响的关键通路，突出了其作为抗贾第虫治疗潜在靶点的重要性。这些发现揭示了ISO2对十二指肠贾第虫的作用模式，并为进一步的药物开发提供了有价值的见解。此外，该研究还为探索异隐品碱衍生物作为贾第虫病的新型治疗药物提供了一条有前景的途径，满足了对更有效、更安全治疗选择的迫切需求。
