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. 2020 Aug 5;184:104881. doi: 10.1016/j.antiviral.2020.104881

Table 2.

In vitro activity of DNJ and DNJ derivatives against members of the Flaviviridae family. References are provided in Fig. 2, Fig. 3, Fig. 4 and details for each study are included in Supplemental Table 2.

Monocyclic Glucose-mimicking Iminosugars
Compound(s) Virus
 Summary of Results
BVDV DENV HCV GBV-B JEV KUN WNV YFV ZIKV
2-THO-DNJ (UV-12) X DENV-2 in Vero cells: IC50 = 27.71 μM, CC50 > 500 μM
CM-9-78 X X DENV-2 in BHK-21 or A549 cells: EC50 = 1.5–6.75 μM, CC50 > 40 μM
HCV chimera in Huh7.5 cells: EC50 = 52.5 μM, CC50 > 500 μM; shift in electrophoresis mobility for E2 and E2-p7 proteins
CM-10-18 (DNJ Derivative 7) X X X All viruses, multiple cell lines: EC50 = 1.1–27.2 μM, CC50 > 100 μM. Synergistic antiviral activity against DENV-2 in A549 cells when combined with ribavirin.
1-Deoxynojirimycin (DNJ) X X X X X X Low activity against most viruses with reported EC50 and EC90 values typically >100 μM. Low cytotoxicity (CC50s reported as >500 to >10,000 μM, depending on cell type and highest concentration tested).
DENV-1 in Neuro 2a cells: E protein misfolding and impaired formation of prME heterodimers
Greater effect on DENV-2 secretion (6 log pfu/mL reduction) at 100 μm/mL compared to JEV (~0.6–1 log pfu/mL reduction) in PS cells
No inhibitory effect observed against KUN in Vero cells at 100 μM
IHVR11029; IHVR17028 X X BVDV in MDBK cells and DENV-2 in BHK-21 cells: EC50 = 0.3–1.3 μM, CC50 > 500 μM
IHVR19029 X X X X Various cell types: EC50 = 0.25–1.7 μM (BVDV, DENV-2) and 21.5–30 μM (YFV, ZIKV), CC50 > 100–500 μM. Synergistic antiviral effect against YFV when used in combination with T-705.
MON-DNJ (UV-4/UV-4B) X DENV 1–4 in Vero cells: IC50 = 2.1–86.49 μM, CC50 > 500-1,000 μM
DENV-2 in MDMs: IC50 = 3.09 μM, CC50 = 3,150 μM
N-5-Oxaheptyl-DNJ (5–07); N-5-Oxahexyl-DNJ (5–06);
N-5-Oxaoctyl-DNJ (5–08);
N-6-Oxadecyl-DNJ (6–10);
N-6-Oxanonyl-DNJ (6–09);
N-6-Oxaocytyl-DNJ (6–08)		 X MDBK cells: 5–07 and 5–06, no antiviral activity (up to 100 μM); 5–08 and 6–10, minimal antiviral activity (up to 100 μM); 6–09 and 6–08, moderate antiviral activity (up to 100 μM) but not improved compared to NN-DNJ. Series not advanced. CC50 > 300 μM for all compounds.
N-7-Oxadecyl-DNJ (UV-3) X X BVDV in MDBK cells: IC50 = 17–80 μM, CC50 > 5,000 μM, reduced secretion of viral RNA in MDBK cells.
DENV-2 in Vero cells: IC50 = 41 μM, CC50 = >500 μM
NAP DNJ (UV-5) X Vero cells: IC50 = 2 μM, CC50 = 350 μM; MDMs: IC50 = 0.04 μM, CC50 = 300 μM
NB-DNJ (UV-1) X X X BVDV in MDBK cells: Large range in IC50s (2.5 to >200 μm), depending on MOI and assay readout. Infecting with lower MOI resulted in lower IC50 across assays; Dose dependent reduction in secretion of infectious virus particles that correlated with misfolding of viral glycoprotein E2; Synergistic when used in combination with IFN-α2b; Treatment of persistently infected MDBK cells in combination with IFN and ribavirin (containing 10 μM NB-DNJ) was sufficient to permanently eliminate virus after 9 passages following drug withdrawal.
HCV chimera/replicon system: Dose dependent decrease in production of infectious particles in Huh7-Lunet and Huh7.5 cells; Reduced electrophoretic mobility of E1 and E2 glycoproteins. In Sf9 cells, E1 and E1 glycoproteins accumulated in ER, had reduced mobility shift, and interaction with calnexin was disrupted.
DENV-2: IC50 = 6–10.6 μM, CC50 > 100 μM (MDMs); IC50 = 162 μM, CC50 > 500 μM (Vero cells)
NN-DNJ (N-nonyl-DNJ/UV-2/DNJ Derivative 6) X X X X X X BVDV in MBDK cells: Range in IC50s depending on assay and publication, with most ranging between 3 and 115 μM, CC50s mostly > 100 μM
DENV-2 in multiple cell lines: IC50 = 1–9 μM, CC50 = 20–317 μM; interfered with prM, E, and NS1 protein interaction with calnexin in BHK-21 cells
HCV in Huh7/Huh7.5/Huh7-Lunet cells: Multiple genotypes evaluated. Dose dependent decrease in production of infectious particles. Reduced electrophoretic mobility shift of E1 and E2 glycoproteins (JFH1 replicon system); inhibition of p7 function for most genotypes tested except for JFH-1/452 (genotype 3a) in which a lower inhibition of infectious particle secretion (only ~40% reduction at 50 μm) and minimal reduction in p7 function were observed. In Sf9 cells using HCV VLPs, E1 and E2 glycoproteins accumulated in ER and had reduced mobility shifts; VLPs produced had reduced binding to huh7 cells.
HCV JFH-1 replicon: Additive effect on reduction of secreted infectious virus when used in combination with Rimantadine.
JEV in BHK-21 cells: Dose dependent inhibition (2–3 log reduction at 100 μM), CC50 = 150 μM; interfered with transient interaction between viral proteins (prM, E, and NS1) and calnexin.
KUN in Vero cells: secreted infectious virus titer reduced by 3.5 log at 100 μM
WNV in BHK-21 cells: IC50 < 4 μM, CC50 = 20–100 μM
OSL-1 (N-Pentylcyclohexyl-DNJ); OSL-3 X X BVDV in MDBK cells: IC50 < 20 μM, CC50 = ~200 μM
WNV in BHK-21 cells: IC50 = 4–10 μM, dose dependent inhibition.
OSL-2 X MDBK cells: IC50 > 70 μM, CC50 > 300 μM
OSL-12-31; OSL-12-51 X MDBK cells: IC50 = ~70 μM (OSL-12-31) or >70 μM (OSL-1-51), CC50 > 300 μM
OSL-95ii X X X X All viruses, various cell lines: IC50 = 2–28 μM (WNV <4 μM), CC50 > 40–500 μM
HCV JC1 chimera in Huh7.5 cells: shift in electrophoresis mobility for E2 and E2-p7 proteins
PBDNJ0801 X X BHK-21 cells: EC50 = 0.1 μM (DENV-2) or 4.75 μM (WNV), CC50 = 70–80 μM
PBDNJ0802 X Huh7.5 cells: EC50 = 3.5 μM, CC50 > 500 μM
PBDNJ0803;
PBDNJ0804		 X X X BHK-21 cells: EC50 = 0.07–0.1 μM (DENV-2) and 1.5–3.5 μM (WNV), CC50 = 65–85 μM
HCV chimera in Huh7.5 cells: EC50 = 1.7–5.4 μM, CC50 > 200 μM, electrophoretic mobility shift and degradation of E2 and E2-p7 proteins (PBDNJ0804)
SP-169; SP-173 X X X BVDV in MDBK cells, DENV-2/WNV in BHK-21 cells: IC50 = 3–5 μM, CC50 > 100 μM
ToP-DNJ X DENV-2: No inhibition observed in Huh7.5 cells (up to 50 μM), IC50 = 12.7 μM in MDMs
DNJ Derivatives 7 - 13 X Reduction in viral RNA and infectious virus secretion measured in MDBK cells.
Derivative 7: no antiviral activity at up to 50 μM
Derivatives 8 and 9: No reduction at 10 μM, 25–75% reduction at 50 μM, CC50 > 250 μM
Derivatives 10 and 11: ~50% reduction at 10 μM, CC50 ≥ 200 μM
Derivatives 12 and 13: ≥75% reduction at 10 μM, CC50 = 29–51 μM
DNJ Derivatives: 1a, 1b; 2b, 2c, 2e, 2f, 2g, 2i, 2j; 3d, 3e, 3f, 3g, 3h, 3i, 3m, 30, 3u; 4d, 4e, 4f; 5a, 5b X Single cycle virus yield reduction plaque assay using MDBK cells:
Derivative 1 compounds: EC50 = 3–7.5 μM, CC50 ≥ 450 μM
Derivative 2 compounds: EC50 = 0.3–1.8 μM, CC50 ≥ 150–500 μM
Derivative 3 compounds: EC50 = 0.4–5.0 μM, CC50 ≥ 62–500 μM
Derivative 4 compounds: EC50 = 3.5–24 μM, CC50 = 295–420 μM
Derivative 5 compounds: EC50 = 11 μM (5a) and >100 μM (5b), CC50 > 500 μM
DNJ Derivatives: 1c, 2a, 2d, 2h, 2k, 2l, 3a, 3b, 3c, 3j, 3k, 3l, 3n, 3p, 3q, 3r, 3s, 3t, 3v, 4a, 4b, 4c, 5d X X BVDV in MDBK cells and DENV-2 in BHK-21 cells: Activity of individual compounds comparable against DENV and BVDV.
Derivative 1 compounds: EC50 = 0.3–0.6 μM, CC50 ≥ 480 μM
Derivative 2, 3, and 4 compounds: EC50 = 0.3–4 μM, CC50 ≥ 400 μM
Derivative 5 compounds: EC50 = 0.9–47 μM, CC50 > 500 μM
SP-116; SP-150; SP-156; SP-159; SP-164; SP-165; SP-166; SP-168; SP-187 X Virus yield reduction using MDBK cells:
SP-165, SP-166, SP-187: IC50 = 3–12 μM, CC50 ≥ 400 μM
SP-116, SP-150, SP-156, SP-159, SP-168: IC50 = 24–40 μM, CC50 ≥ 500 μM
SP-164: IC50 = 150 μM, CC50 > 1,000 μM

Abbreviations: BVDV, bovine viral diarrhea virus; CC50, 50% cytotoxic concentration; DENV, dengue virus; EC50, half maximal effective concentration; ER, endoplasmic reticulum; GBV-B, GB virus B; HCV, hepatitis C virus; IC50, half maximal inhibitory concentration; IFN, interferon; JEV, Japanese encephalitis virus; KUN, Kunjin virus; MDBK, Madin-Darby bovine kidney; MDM, monocyte-derived macrophages; MOI, multiplicity of infection; PS, porcine stable; pfu, plaque-forming unit; prM: precursor membrane protein; prME: precursor membrane-envelope protein complex; VLP, virus-like particle; WNV, West Nile virus; YFV, yellow fever virus; ZIKV, zika virus.