Epoxomicin

Epoxomicin is a selective proteasome inhibitor that effectively inhibits the chymotrypsin-like (CH-L) activity of the 20S proteasome, with an IC₅₀ of approximately 40-80nM^[1]. Epoxomicin covalently binds to the catalytic β subunits LMP 7, X, Z, and MECL 1 of the proteasome, leading to inhibition of the proteasome subunits' CH-L, T-L, and PGPH catalytic activities^[2].

In vitro, Epoxomicin shows considerable cytotoxicity against B16-F10, HCT116, Moser, P388, and K562 cells, with IC₅₀ values of 0.002μg/mL, 0.005μg/mL, 0.044μg/mL, 0.002μg/mL, and 0.037μg/mL, respectively^[3]. Epoxymycin (0.2 and 2 μM) treated HEK293T cells for 1 hour, inhibiting the expression of proteasome beta-2 and beta-5 subunits in the cells^[4]. Epoxomicin (100 nM) for 24 hours in Plasmodium falciparum cells results in a 77% reduction in gametocytes^[5].

In vivo, Epoxymycin (0.5mg/kg), administered intraperitoneally, reduced polyubiquitination in GAS muscle of C57BL/6 mice by 23% and increased polyubiquitination in liver by 41%, the latter associated with The inhibitory effect of proteasome β5 is consistent ^[6]. Epoxymycin (0.5mg/kg/day) was administered to KI and WT mice for 1 week using a subcutaneously implanted osmotic minipump, which reduced the chymotrypsin-like activity of the mice by approximately 50%^[7] .

References:

[1] Meng L , Mohan R , Kwok B H B ,et al.Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity[J]. Proceedings of the National Academy of Sciences, 1999, 96(18):10403-10408.

[2] Aboulaila M , Nakamura K , Govind Y ,et al.Evaluation of the in vitro growth-inhibitory effect of epoxomicin on Babesia parasites.[J].Veterinary Parasitology, 2010, 167(1):19-27.

[3] Hanada M,  Sugawara K, Kaneta K, et al. Epoxomicin, a new antitumor agent of microbial origin.[J] Antibiot (Tokyo). 1992 Nov;45(11):1746-52.

[4] Fricker L D, Gelman J S, Castro L M, et al. Peptidomic analysis of HEK293T cells: effect of the proteasome inhibitor epoxomicin on intracellular peptides[J]. Journal of proteome research, 2012, 11(3): 1981-1990.

[5] Czesny B , Goshu S , Cook J L ,et al. The Proteasome Inhibitor Epoxomicin Has Potent Gametocytocidal Activity[J]. 2009.

[6]Jamart, Cécile, Gomes A V , Dewey S ,et al. Regulation of ubiquitin-proteasome and autophagy pathways after acute LPS and epoxomicin administration in mice[J].Bmc Musculoskeletal Disorders, 2014, 15(1):166.

[7]Schlossarek,Saskia,Singh,et al. Proteasome inhibition slightly improves cardiac function in mice with hypertrophic cardiomyopathy[J].Frontiers in Physiology, 2014.

环氧霉素（Epoxomicin）是一种选择性蛋白酶体抑制剂，有效地抑制20S蛋白酶体的胰凝乳蛋白酶样（CH-L）活性，IC₅₀约为40-80nM^[1]。环氧霉素共价结合蛋白酶体的LMP 7、X、Z和MECL 1催化β亚基，导致蛋白酶体亚基的CH-L、T-L和PGPH催化活性受到抑制^[2]。

在体外，环氧霉素对B16-F10、HCT116、Moser、P388和K562细胞均显示出相当强的细胞毒性，IC₅₀ 值分为 0.002 μg/mL、0.005 μg/mL、0.044 μg/mL、0.002 μg/mL和0.037μg/mL^[3]。环氧霉素(0.2和2μM)处理HEK293T细胞1小时，抑制了细胞中的蛋白酶体beta-2和beta-5亚基的表达^[4]。环氧霉素(100 nM)处理恶性疟原虫细胞24小时，配子细胞减少了77%^[5]。

在体内，环氧霉素（0.5mg/kg）通过腹腔注射，使C57BL/6小鼠GAS肌肉中的多泛素化降低 23%，使肝脏中的多泛素化增加 41%，后者与蛋白酶体β5抑制作用一致^[6]。环氧霉素（0.5mg/kg/天）采用皮下植入的渗透微型泵持续1周对KI和WT小鼠 给药，使小鼠的胰凝乳蛋白酶样活性降低了约50%^[7]。