Kifunensine (Synonyms: FR900494)

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 K_i 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.