Table 1.
Iminosugars targeting ER α-glucosidases have been tested in vitro against a range of INFV strains, resulting in effects on viral glycoproteins and virion production.
| Iminosugar; concentration | INFV strain | Cell line | Viral glycoprotein processing inhibition | Reference |
|---|---|---|---|---|
| Inhibition of virion production or infectivity | ||||
| Swainsonine | ||||
| 1 μg/ml | A/fowl plague virus/Rostock/34 (H7N1) | Primary calf kidney | Complex glycan formation (10% of control) and high-mannose oligosaccharide processing | Elbein et al. (1982) |
| No effect on infectivity or hemagglutination | ||||
| 0.005–5 μg/ml | A/NWS/33 (H1N1) | MDCK | Glucose trimming | Merkle et al. (1985) |
| No effect on hemagglutination | ||||
| 25, 100 ng/ml | A/NWS/33 (H1N1) | MDCK | Fucosylated hybrid oligosaccharides produced; no effect on sulfation | Schwarz & Elbein (1985) |
| Not tested | ||||
| Castanospermine (CAST) | ||||
| 10 μg/ml | A/NWS/33 (H1N1) | MDCK | Complex glycan formation | Pan et al. (1983) |
| None | ||||
| 10–500 μg/ml | A/NWS/33 (H1N1) | MDCK | Glucose trimming and sulfation | Merkle et al. (1985) |
| No effect on hemagglutination | ||||
| 25, 100 μg/ml | A/NWS/33 (H1N1) | MDCK | Glucose trimming and sulfation | Schwarz & Elbein (1985) |
| Not tested | ||||
| 1 mM | A/HKx31 (H3N2) | CHO 15B | HA glucose trimming and CNX binding | Hammond et al. (1994) |
| Not tested | ||||
| 200 μg/ml | A/NWS/33 (H1N1) | MDCK | HA glucose trimming | Kaushal et al. (1988) |
| Not tested | ||||
| 200 μg/ml | A/HKx31 (H3N2) | CI42 | HA glucose trimming and CNX binding | Ermonval et al. (2000) |
| Not tested | ||||
| 200 μg/ml | A/HKx31 (H3N2) | B3F7 AP2-1 | HA glucose trimming and CNX binding | |
| Not tested | ||||
| 200 μg/ml | A/HKx31 (H3N2) | MadI A214 | No inhibition of HA glucose trimming or CNX binding | |
| Not tested | ||||
| 1 mM | Reassortant virus NWS-duck/Ukraine/1/63 (H1N8) | MDCK | NA secretion 50% of control; HA unaffected. NA activity 50% and HA titer >50% of control | Saito & Yamaguchi (2000) |
| PFU 30% of control | ||||
| 12, 25, 50, 100, 200 μM | A/Hong Kong/11/88 (sic) | MDCK | Not tested | Tyms & Virogen Ltd (2003) |
| IC50 15 μM | ||||
| 6-O-butanoyl-castanospermine (BuCAST) | ||||
| 0.2 mM | A/Puerto Rico/8/34 (H1N1) | MDCK | HA processing by endomannosidase | Karaivanova et al. (1998) |
| No effect on production | ||||
| 6, 12, 25, 50, 100 μM | A/Hong Kong/11/88 | MDCK | Not tested | Tyms and Virogen Ltd (2003) |
| IC50 <6 μM | ||||
| 2,5-dihydroxymethyl-3,4-dihydroxypyrrolidine (DMDP) | ||||
| 5, 50, 250 μg/ml | A/NWS/33 (H1N1) | MDCK | Glucose trimming | Elbein et al. (1984b) |
| Not tested | ||||
| 1-deoxynojirimycin (DNJ) a | ||||
| 2 mM | A/chick/Germany/49 (H10N7) | MDCK | Surface HA expression unaffected | Burke et al. (1984) |
| Infectivity by approximately 30%. No effect on production | ||||
| 10 mM | A/fowl plague virus/Rostock/34 (H7N1) | MDCK | Not tested | Huang et al. (1991) |
| Hemagglutination and CPE (complete) | ||||
| 1 mM | A/HKx31 (H3N2) | CHO 15B | Glucose trimming and CNX binding | Hammond et al. (1994) |
| Not tested | ||||
| 1 mM | Reassortant virus NWS-duck/Ukraine/1/63 (H1N8) | MDCK | NA activity >40% of control and HA titer >40% of control | Saito & Yamaguchi (2000) |
| PFU 30% of control | ||||
| N-methyl-1-deoxynojirimycin (NM-DNJ) | ||||
| 0.5, 1 mM | A/fowl plague virus/Rostock/34 (H7N1) | CEC | HA cleaved | Romero et al. (1983) |
| No effect on virion release | ||||
| 2 mM | H7 strains | CEC | Glucose trimming | Bosch et al. (1984) |
| No effect on infectivity | ||||
| N-butyl-deoxynojirimycin (NB-DNJ) | ||||
| Titration | A/Udorn/307/72 (H3N2) | MDCK | Not tested | Hussain et al. (2015) |
| HA titer: IC50 21.7 ± 15.9 μM, IC90 280.0 ± 23.6 μM. Infectivity: IC50 34.7 ± 11.2 μM, IC90 296.1 ± 16.1 μM. | ||||
| Titration | A/Brisbane/10/2007 (H3N2) | MDCK | Not tested | |
| HA titer: IC50 43.8 ± 6.5 μM, IC90 207.0 ± 95.3 μM. Infectivity: IC50 43.6 ± 11.8 μM, IC90 250.0 ± 10.4 μM. | ||||
| Titration | A/Lviv/N6/2009 (H1N1) | MDCK | Not tested | |
| HA titer: IC50 51.3 ± 11.3 μM, IC90 >312.5 μM. Infectivity: IC50 46.5 ± 12.2 μM, IC90 >312.5 μM. | ||||
| N-nonyl-deoxynojirimycin (NN-DNJ) | ||||
| Titration for IC50 and IC90 determination, otherwise 62.5 μM | A/Udorn/307/72 (H3N2) | MDCK | HA secretion. NA sialidase activity (by 35–45%). 26.4% triglucosylated HA glycans | Hussain et al. (2015) |
| HA titer 6-8% of control. Infectivity: IC50 0.4 ± 0.2 μM, IC90 16.2 ± 4.7 μM. Plaque number: IC50 >62.5 μM. Plaque size: IC50 6.6 ± 5.5 μM, IC90 >62.5 μM, not restored with exogenous NA | ||||
| Titration for IC50 and IC90 determination, otherwise 62.5 μM | A/Brisbane/10/2007 (H3N2) | MDCK | HA secretion. NA sialidase activity (by 30–40%). 21.8% triglucosylated HA glycans | |
| HA titer 0% of control. Infectivity: IC50 1.73 ± 0.3 μM, IC90 10.3 ± 0.3 μM. Plaque number: IC50 8.2 ± 2.4 μM, IC90 22.0 ± 9.5 μM. Plaque size: IC50 4.1 ± 1.2 μM, IC90 10.9 ± 0.3 μM, not restored with exogenous NA | ||||
| Titration for IC50 and IC90 determination, otherwise 62.5 μM | A/Lviv/N6/2009 (H1N1) | MDCK | No effect on surface HA or NA. NA sialidase activity (by 45–60%). 37.3% triglucosylated HA glycans | |
| HA titer 13–25% of control. Infectivity: IC50 1.9 ± 0.8 μM, IC90 >62.5 μM. Plaque number: IC50 >62.5 μM. Plaque size: IC50 1.8 ± 0.3 μM, IC90 >62.5 μM, not restored with exogenous NA | ||||
| Titration | Reassortant X-181 (H1N1) | MDCK | Not tested | |
| IC50 >62.5 μM | ||||
| Titration | Reassortant X-171b (H3N2) | MDCK | Not tested | |
| IC50 0.4 ± 0.1 μM, IC90 2.4 ± 0.5 μM | ||||
| Titration | Reassortant A/Brisbane/10/2007 (H3N1) with A/Lviv/N6/2009 NA | MDCK | Not tested | |
| Plaque number: IC50 9.2 ± 1.7 μM, IC90 55.0 ± 6.8 μM. Plaque size: IC50 5.8 ± 1.2 μM, IC90 14.3 ± 2.7 μM. Effects greater relative to A/Lviv/N6/2009 and comparable to A/Brisbane/10/2007 | ||||
| N-8′-(2′′-tetrahydrofuranyl)-octyl-deoxynojirimycin (2THO-DNJ, UV-12) | ||||
| Titration <250 μM | A/Texas/36/91 (H1N1) | MDCK | Not tested | Warfield et al. (2015) |
| Infectivity: IC50 >250 μM | ||||
| N-(9-methoxynonyl)-1-deoxynojirimycin (MON-DNJ, UV-4) | ||||
| Titration | A/Texas/36/91 (H1N1) | MDCK | Not tested | Warfield et al. (2016) |
| IC50 >125 μM | ||||
| Titration | A/California/07/2009 (H1N1) | MDCK | Not tested | |
| IC50 >125 μM | ||||
| Titration | A/Mississippi/3/2001 (H1N1) | MDCK | Not tested | |
| IC50 >125 μM | ||||
| Titration | A/Mississippi/3/2001 H275Y (H1N1) | MDCK | Not tested | |
| IC50 >125 μM | ||||
| Titration | A/Hong Kong/68 (H3N2) | MDCK | Not tested | |
| IC50 6.01 μM | ||||
| Titration | A/Perth/16/2009 (H3N2) | MDCK | Not tested | |
| IC50 63.9 μM | ||||
| Titration | A/Victoria/361/2011 (H3N2) | MDCK | Not tested | |
| IC50 3.75 μM | ||||
| Titration | A/Victoria/3/75 (H3N2) | MDCK | Not tested | |
| IC50 >84.9 μM | ||||
| Titration | A/Philippines/2/82 (H3N2) | MDCK | Not tested | |
| IC50 >250 μM | ||||
| Titration | B/Lee/40 | MDCK | Not tested | |
| IC50 >125 μM | ||||
| Titration | B/Brisbane/60/2008 | MDCK | Not tested | |
| IC50 >125 μM | ||||
| Titration | B/Wisconsin/01/2010 | MDCK | Not tested | |
| IC50 >125 μM | ||||
| Titration | A/California/07/2009 (H1N1) | dNHBE | Not tested | |
| IC90 >320 μM | ||||
| Titration | A/California/12/2012 (H1N1) | dNHBE | Not tested | |
| IC90 320 μM; 219 μM | ||||
| Titration | A/Victoria/3/75 (H3N2) | dNHBE | Not tested | |
| IC90 440 μM; 483 μM | ||||
| Titration | A/Texas/50/2012 (H3N2) | dNHBE | Not tested | |
| IC90 82 μM | ||||
| Titration | B/Brisbane/60/2008 | dNHBE | Not tested | |
| IC90 200 μM | ||||
| Titration | B/Florida/4/2006 | dNHBE | Not tested | |
| IC90 150 μM | ||||
| Titration | B/Massachusetts/2/2012 | dNHBE | Not tested | |
| IC90 209 μM; 245 μM | ||||
| Titration | B/Malaysia/2506/2004 | dNHBE | Not tested | |
| IC90 >500 μM | ||||
| N-benzyl-1,5-dideoxy-1,5-imino-d-glucitol | ||||
| 10 mM | A/fowl plague virus/Rostock/34 (H7N1) | MDCK | Not tested | Huang et al. (1991) |
| Hemagglutination (partial) | ||||
| N,2-O-dibenzyl-1,5-dideoxy-1,5-imino-d-glucitol | ||||
| 10 mM | A/fowl plague virus/Rostock/34 (H7N1) | MDCK | Not tested | Huang et al. (1991) |
| Hemagglutination and CPE (complete) | ||||
| Homonojirimycin (HNJ) | ||||
| 100, 200 μg/ml | A/NWS/33 (H1N1) | MDCK | HA high-mannose oligosaccharide processing | Zeng et al. (1997) |
| Not tested | ||||
| Titration | A/Puerto Rico/8/34 (H1N1) | MDCK | Not tested | Zhang, et al. (2013) |
| Infectivity: IC50 10.4 μg/ml in CPE reduction assay | ||||
| N-methyl-α-homonojirimycin (NM-HNJ) | ||||
| 25, 100 μg/ml | A/NWS/33 (H1N1) | MDCK | 25 μg/ml: HA high-mannose oligosaccharide processing (5-fold) 100 μg/ml: HA high-mannose oligosaccharide processing (complete) |
Zeng et al. (1997) |
| Not tested | ||||
B3F7AP2–1 and MadIA214: glycosylation-defective CHO cells; CEC: chicken-embryo cell; CI42: parental CHO cell; CPE: cytopathic effect; dNHBE: differentiated normal human bronchial epithelial; HA titer: haemagglutination titer; IC50 or IC90: drug concentration required to inhibit by 50% or 90%, respectively.
a
DNJ cannot be considered a specific inhibitor of α-glucosidases since it also inhibits the formation of dolichol-linked oligosaccharides required for N-linked glycosylation (Datema et al., 1984).