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. 2018 Jan 19;13(1):60-65.
doi: 10.1021/acschembio.7b00870. Epub 2017 Dec 5.

ToP-DNJ, a Selective Inhibitor of Endoplasmic Reticulum α-Glucosidase II Exhibiting Antiflaviviral Activity

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ToP-DNJ, a Selective Inhibitor of Endoplasmic Reticulum α-Glucosidase II Exhibiting Antiflaviviral Activity

J L Kiappes et al. ACS Chem Biol. .
Free PMC article

Abstract

Iminosugars have therapeutic potential against a range of diseases, due to their efficacy as glycosidase inhibitors. A major challenge in the development of iminosugar drugs lies in making a compound that is selective for the glycosidase associated with a given disease. We report the synthesis of ToP-DNJ, an antiviral iminosugar-tocopherol conjugate. Tocopherol was incorporated into the design of the iminosugar in order to direct the drug to the liver and immune cells, specific tissues of interest for antiviral therapy. ToP-DNJ inhibits ER α-glucosidase II at low micromolar concentrations and selectively accumulates in the liver in vivo. In cellular assays, the drug showed efficacy exclusively in immune cells of the myeloid lineage. Taken together, these data demonstrate that inclusion of a native metabolite into an iminosugar provides selectivity with respect to target enzyme, target cell, and target tissue.

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Enzyme targets and structures of iminosugars. (A) Trimming of the N-glycan by ER α-glucosidases I and II (GluI and GluII). (B) d-1-Deoxynojirimycin 1 and N-butyl-d-1-deoxynojirimycin 2 inhibit the ER-resident enzymes GluI (PDB ID 4J5T), GluII (PDB ID 5F0E), and intestinal glucosidases (e.g., maltase/glucoamylase, PDB ID 3TOP), which, like GluII, are members of glycoside hydrolase family 31. (C) d-(+)-α-tocopherol 3 and ToP-DNJ 4.
Scheme 1
Scheme 1. Synthesis of ToP-DNJ 4
Figure 2
Figure 2
Effects of ToP-DNJ 4 treatment in monocyte-derived macrophages (MDMΦ). (A) Protein-normalized free oligosaccharide levels of naive MDMΦ (1 representative donor). The bar represents the mean; error bars show one standard deviation. (B) Infectious virus titer produced by dengue-infected MDMΦ (7 donors) under ToP-DNJ 4 or α-tocopherol 3 treatment. Compound 4 has an IC50 of 12.7 μM, while 3 showed no antiviral effect. The data points represent the mean; error bars show standard error of the mean.
Figure 3
Figure 3
In vivo studies of ToP-DNJ 4 in BALB/c mice. (A) The concentration of 4 in all organs after intravenous (IV) administration. (B) Serum concentration of 4 over time (IV and per os, PO). On both graphs, the mean of 3 animals is shown; error bars show one standard deviation.

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