Kifunensine (FR900494) is a potent mannosidase I inhibitor that effectively inhibits the activities of endoplasmic reticulum α-1,2-mannosidase I (MAN1B1) and class I mannosidase Golgi subfamily (Golgi α-mannosidase IA, IB, and IC) with Ki values of 130 and 23 nM, respectively. Kifunensine also inhibits mung bean α-1,2-mannosidase I with IC50 values of 20-50 nM [1, 2]. Kifunensine inhibits the endoplasmic reticulum-associated degradation (ERAD) pathway and prevents glycosylation trimming of misfolded glycoproteins [3].
In vitro, kifunensine (1, 10, 50 µM) treatment of OVCAR8 cells for 72 h strongly inhibited spheroid formation at a low concentration of 1 μM and dose-dependently induced mass shift of the N-glycosylated adhesion molecule ALCAM protein in the cells, causing the protein to accumulate in the cytoplasm[4]. Kifunensine (10 µM) treatment of MDA-MB-231 and T47D cells for 48 h resulted in mass transfer of N-glycosylated adhesion molecules ALCAM, ICAM-1, and BCAM[5]. Kifunensine (20 μg/mL) treatment of mesenchymal stromal cells (MSCs) induced an increase in angiopoietin 2 levels and significantly increased cell proliferation when cultured for up to six days[6].
In vivo, oral treatment of triptan knockout mice with kifunensine (4 mg/kg) for 12 days increased the expression level of calcium chelator 2 (CSQ2) to 117% ± 32% and reversed electrocardiographic abnormalities[7].
References:
[1] Soheili T, Gicquel E, Poupiot J, et al. Rescue of sarcoglycan mutations by inhibition of endoplasmic reticulum quality control is associated with minimal structural modifications[J]. Human mutation, 2012, 33(2): 429-439.
[2] Bartoli M, Gicquel E, Barrault L, et al. Mannosidase I inhibition rescues the human α-sarcoglycan R77C recurrent mutation[J]. Human molecular genetics, 2008, 17(9): 1214-1221.
[3] Seidel E, Dassa L, Kahlon S, et al. A slowly cleaved viral signal peptide acts as a protein-integral immune evasion domain[J]. Nature communications, 2021, 12(1): 2061.
[4] Hamester F, Legler K, Wichert B, et al. Prognostic relevance of the Golgi mannosidase MAN1A1 in ovarian cancer: impact of N-glycosylation on tumour cell aggregation[J]. British Journal of Cancer, 2019, 121(11): 944-953.
[5] Legler K, Rosprim R, Karius T, et al. Reduced mannosidase MAN1A1 expression leads to aberrant N-glycosylation and impaired survival in breast cancer[J]. British journal of cancer, 2018, 118(6): 847-856.
[6] Alonso-Garcia V, Chaboya C, Li Q, et al. High mannose N-glycans promote migration of bone-marrow-derived mesenchymal stromal cells[J]. International journal of molecular sciences, 2020, 21(19): 7194.
[7] Cacheux M, Fauconnier J, Thireau J, et al. Interplay between triadin and calsequestrin in the pathogenesis of CPVT in the mouse[J]. Molecular Therapy, 2020, 28(1): 171-179.
Kifunensine（FR900494）是一种有效的甘露糖苷酶I抑制剂，能够有效抑制内质网α-1,2-甘露糖苷酶I（MAN1B1）和I类甘露糖苷酶高尔基体亚家族（高尔基体α-甘露糖苷酶IA、IB和IC）的活性，Ki值分别为130和23nM。Kifunensine还抑制绿豆 α-1,2-甘露糖苷酶I，IC50 值为20-50nM[1, 2]。Kifunensine可抑制内质网相关降解（ERAD）途径，防止错误折叠糖蛋白的糖基化修剪[3]。
在体外，Kifunensine（1，10，50µM）处理OVCAR8细胞72h，在低浓度1μM下强烈抑制球状体的形成，剂量依赖性地导致细胞中N-糖基化粘附分子ALCAM蛋白发生了质量转移，使该蛋白质在细胞质中积累[4]。Kifunensine（10µM）处理MDA-MB-231和T47D细胞48h，N-糖基化粘附分子ALCAM、ICAM-1和BCAM均发生了质量转移[5]。Kifunensine（20 μg/mL）处理间充质基质细胞（MSC），诱导血管生成素2水平增加，在连续培养长达六天时细胞增殖显著增加[6]。
在体内，Kifunensine（4mg/kg）通过口服治疗三联蛋白敲除小鼠12天，提高了钙螯合蛋白2（CSQ2）表达水平，使其增加至117%±32%，逆转了心电图异常[7]。