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呋马硝唑通过与甲硫氨酸氨肽酶 2 共价结合并选择性抑制其活性来抑制肠道原生动物寄生虫的生长。

Fumagillin inhibits growth of the enteric protozoan parasite by covalently binding to and selectively inhibiting methionine aminopeptidase 2.

机构信息

Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo , Tokyo, Japan.

Department of Parasitology and Antimicrobial Resistance Research Center, National Institute of Infectious Diseases , Tokyo, Japan.

出版信息

Antimicrob Agents Chemother. 2023 Nov 15;67(11):e0056023. doi: 10.1128/aac.00560-23. Epub 2023 Oct 24.

Abstract

Amebiasis is an important cause of morbidity and mortality worldwide, and caused by infection with the protozoan parasite . Metronidazole is currently the first-line drug despite adverse effects and concerns on the emergence of drug resistance. Fumagillin, a fungal metabolite from and its structurally related natural and synthetic compounds have been previously explored as potential anti-angiogenesis inhibitors for cancers, anti-microbial, and anti-obese compounds. Although fumagillin was used for human amebiasis in clinical trials in 1950s, the mode of action of fumagillin remains elusive until now. In this report, we showed that fumagillin covalently binds to methionine aminopeptidase 2 (MetAP2) and non-covalently but abundantly binds to patatin family phospholipase A (PLA). Susceptibility against fumagillin of the amebic strains in which expression of () gene was silenced increased compared to control strain. Conversely, overexpression of EhMetAP2 mutants that harbors amino acid substitutions responsible for resistance to ovalicin, a fumagillin analog, in human MetAP2, also resulted in decrease in fumagillin susceptibility. In contrast, neither gene silencing nor overexpression of PLA (EhPLA) affected fumagillin susceptibility. These data suggest that EhPLA is not essential and not the target of fumagillin for its amebicidal activity. Taken together, our data have demonstrated that EhMetAP2 is the primary target for amebicidal activity of fumagillin, and EhMetAP2 represents a rational explorable target for the development of alternative therapeutic agents against amebiasis.

摘要

溶组织内阿米巴病是全世界发病率和死亡率的重要原因,由原生动物寄生虫感染引起。尽管存在不良反应和对耐药性出现的担忧,但甲硝唑目前仍是一线药物。尽管过去曾将来自 和其结构相关的天然和合成化合物的真菌代谢物呋咱并噻唑作为癌症的潜在抗血管生成抑制剂、抗微生物和抗肥胖化合物进行了研究,但呋咱仍被用于 20 世纪 50 年代的人体阿米巴病临床试验。直到现在,呋咱的作用机制仍不清楚。在本报告中,我们表明呋咱与蛋氨酸氨肽酶 2(MetAP2)共价结合,并且与类脂酶 A(PLA)非共价但大量结合。与对照株相比,表达 ()基因的阿米巴株对呋咱的敏感性增加。相反,对在人类 MetAP2 中携带导致对 ovalicin(呋咱类似物)耐药的氨基酸取代的 EhMetAP2 突变体的过表达也导致对呋咱的敏感性降低。相比之下,EhPLA(EhPLA)基因沉默或过表达均不影响呋咱的敏感性。这些数据表明 EhPLA 不是其杀阿米巴活性的必需靶标,也不是呋咱的靶标。总之,我们的数据表明 EhMetAP2 是呋咱杀阿米巴活性的主要靶标,EhMetAP2 代表了开发抗阿米巴病替代治疗药物的合理探索靶标。

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