Imino sugars that are less toxic but more potent as antivirals, in vitro, compared with N-n-nonyl DNJ (original) (raw)
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Novel imino sugar α-glucosidase inhibitors as antiviral compounds
Bioorganic & Medicinal Chemistry, 2013
Deoxynojirimycin (DNJ) based imino sugars display antiviral activity in the tissue culture surrogate model of Hepatitis C (HCV), bovine viral diarrhoea virus (BVDV), mediated by inhibition of ER a-glucosidases. Here, the antiviral activities of neoglycoconjugates derived from deoxynojirimycin, and a novel compound derived from deoxygalactonojirimycin, by click chemistry with functionalised adamantanes are presented. Their antiviral potency, in terms of both viral infectivity and virion secretion, with respect to their effect on a-glucosidase inhibition, are reported. The distinct correlation between the ability of long alkyl chain derivatives to inhibit ER a-glucosidases and their anti-viral effect is demonstrated. Increasing alkyl linker length between DNJ and triazole groups increases a-glucosidase inhibition and reduces the production of viral progeny RNA and the maturation of the envelope polypeptide. Disruption to viral glycoprotein processing, with increased glucosylation on BVDV E2 species, is representative of a-glucosidase inhibition, whilst derivatives with longer alkyl linkers also show a further decrease in infectivity of secreted virions, an effect proposed to be distinct from a-glucosidase inhibition.
Journal of Virology, 2001
The glucose-derived iminosugar derivatives N-butyl-and N-nonyl-deoxynojirimycin (DNJ) have an antiviral effect against a broad spectrum of viruses including Bovine viral diarrhea virus (BVDV). For BVDV, this effect has been attributed to the reduction of viral secretion due to an impairment of viral morphogenesis caused by the ability of DNJ-based iminosugar derivatives to inhibit ER ␣-glucosidases (N). Here we present the antiviral features of newly designed DNJ derivatives and report for the first time the antiviral activity of long-alkyl-chain derivatives of deoxygalactonojirimycin (DGJ), a class of iminosugars derived from galactose which does not inhibit endoplasmic reticulum (ER) ␣-glucosidases. We demonstrate the lack of correlation between the ability of long-alkyl-chain DNJ derivatives to inhibit ER ␣-glucosidases and their antiviral effect, ruling out ER ␣-glucosidase inhibition as the sole mechanism responsible. Using short-and long-alkyl-chain DNJ and DGJ derivatives, we investigated the mechanisms of action of these drugs. First, we excluded their potential action at the level of the replication, protein synthesis, and protein processing. Second, we demonstrated that DNJ derivatives cause both a reduction in viral secretion and a reduction in the infectivity of newly released viral particles. Long-alkyl-chain DGJ derivatives exert their antiviral effect solely via the production of viral particles with reduced infectivity. We demonstrate that long-alkyl-chain DNJ and DGJ derivatives induce an increase in the quantity of E2-E2 dimers accumulated within the ER. The subsequent enrichment of these homodimers in secreted virus particles correlates with their reduced infectivity. Cells, viruses, and inhibitors. Madin-Darby bovine kidney (MDBK) cells were maintained at 37°C in a humidified, 5% CO 2 atmosphere in RPMI 1640 medium (GIBCO/BRL) supplemented with 10% screened BVDV-free fetal calf serum (PAA Laboratories, Teddington, United Kingdom). The noncytopathic (ncp) Pe515 strain (23) and the cytopathic (cp) NADL (National Animal Disease Laboratory) strain were used in this study. The titers of the stock solutions of these viruses were determined to be 4 ϫ 10 6 and 2 ϫ 10 7 PFU/ml, respectively. NB-DNJ was a gift from Searle/Monsanto. NN-DGJ was purchased from Toronto Research Chemicals. 6-Deoxy-DGJ was kindly provided by G. W. Fleet (University of Oxford). NN-DNJ, N-nonyl-6-deoxy-DGJ, N7-oxadecyl-DNJ and N7-oxanonyl-6-deoxy-DGJ were either synthesized in-house or provided by Synergy Pharmaceuticals Inc.
Antiviral Research, 2010
Classical swine fever virus glycoproteins: E2, E rns (E0) and E1 are detected on the external part of viral particles and play a major role in the initial stages of viral infection. They form heterodimeric and homodimeric complexes needed to effectively infect host cells. Some glycosylation inhibitors, such as tunicamycin, which act at the early stages of glycan chain processing, can influence, not only glycosylation, but also the stability of E2 and E rns glycoproteins, effectively inhibiting the formation of glycoprotein complexes and virus yield. In our study we tested two of newly designed uridine derivatives of 2-deoxy sugars, IW3 and IW7 mimicking part of tunicamycin. We showed that inhibitors effectively arrest viral growth with IC 50 of 9 and 7 g/ml respectively, without significant toxicity for mammalian cells. Moreover, IW3 and IW7 reduced the formation of viral glycoproteins E2 and E rns in a dose-dependent manner. These compounds were further studied in order to elucidate the molecular mechanism of the antiviral effect using mammalian SK6 and insect Sf9 cell lines. We found that they inhibit N-glycosylation process of viral proteins at the late stage of glycan modification characteristic for mammalian cells. Due to the observed antiviral effect accompanied by low cytotoxicity, these inhibitors are potential candidates for anti-pestivirus therapy.
Antiviral chemistry & chemotherapy, 2007
The antiviral activity of iminocyclitol compounds with a deoxynojirimycin (DNJ) head group and either a straight chain alkyl or alkylcycloalkyl group attached to the nitrogen atom have been tested in vitro against multiple-enveloped viruses. Several of these analogues were superior to previously reported DNJ compounds. Iminocyclitols that inhibit the glycan-processing enzyme endoplasmic-reticular glucosidase have been shown to inhibit the morphogenesis of viruses that bud from the endoplasmic reticulum (ER) at non-cytotoxic concentrations. Bovine viral diarrhoea virus (BVDV) has been used as a surrogate system for study of the hepatitis C virus, which belong to the virus family (Flaviviridae) as West Nile virus (WNV) and dengue virus (DV). N-Nonyl-DNJ (NNDNJ) was previously reported to have micromolar antiviral activity against BVDV, but a limiting toxicity profile. N-Butylcyclohexyl-DNJ (SP169) was shown to be as potent as NNDNJ in assays against BVDV and less toxic. However, it wa...
Structure-Activity Relationship of a New Class of Anti-Hepatitis B Virus Agents
Antimicrobial Agents and Chemotherapy, 2002
N -Nonyl-deoxy-galactonojirimycin ( N -nonyl-DGJ) has been shown to reduce the amount of hepatitis B virus (HBV) produced by tissue cultures under conditions where cell viability is not affected. We show here that the compound N -nonyl-DGJ was effective against lamivudine-resistant HBV mutants bearing the YMDD motif in the polymerase gene, consistent with the compound's activity being distinct from those of nucleoside inhibitors. To better understand the chemical structures that influence its antiviral activity, a series of imino sugar derivatives were made and tested for their antiviral activity against HBV. This work suggests that the antiviral activity of the alkovirs requires an alkyl chain length of at least eight carbons but that the galactose-based head group can be modified with little or no loss in activity.
Iminosugars: Effects of Stereochemistry, Ring Size, and N-Substituents on Glucosidase Activities
Pharmaceuticals
N-substituted iminosugar analogues are potent inhibitors of glucosidases and glycosyltransferases with broad therapeutic applications, such as treatment of diabetes and Gaucher disease, immunosuppressive activities, and antibacterial and antiviral effects against HIV, HPV, hepatitis C, bovine diarrhea (BVDV), Ebola (EBOV) and Marburg viruses (MARV), influenza, Zika, and dengue virus. Based on our previous work on functionalized isomeric 1,5-dideoxy-1,5-imino-D-gulitol (L-gulo-piperidines, with inverted configuration at C-2 and C-5 in respect to glucose or deoxynojirimycin (DNJ)) and 1,6-dideoxy-1,6-imino-D-mannitol (D-manno-azepane derivatives) cores N-linked to different sites of glucopyranose units, we continue our studies on these alternative iminosugars bearing simple N-alkyl chains instead of glucose to understand if these easily accessed scaffolds could preserve the inhibition profile of the corresponding glucose-based N-alkyl derivatives as DNJ cores found in miglustat and mi...
ACS chemical biology, 2018
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.
Effects of the imino sugar N-butyldeoxynojirimycin on the N-glycosylation of recombinant gp120
Journal of Biological Chemistry, 1993
The imino sugar N-butyldeoxynojirimycin (NB-DNJ) exhibits anti-HIV activity in vitro and inhibits the purified glycoprocessing enzyme al,2-glucosidase I. It has been speculated that the anti-viral activity of this compound may result from inhibition of HIV envelope glycoprotein processing. However, structural evidence that glucosidase inhibition takes place in intact cells at the anti-viral concentration (0.5 mM) is lacking. In this study, N-linked glycosylation of recombinant gp120 expressed in Chinese hamster ovary cells cultured in the presence or absence of NB-DNJ has been characterized. Immunoprecipitation, in conjunction with endoglycosidase H (endo H) digestion and SDSpolyacrylamide gel electrophoresis analysis, revealed that the glycosylation of gp120 was profoundly altered in the presence of NB-DNJ. The majority of the gp120 oligosaccharides from untreated cells were resistant to endo H. However, nearly complete endo H sensitivity was observed following treatment with 0.5 mM NB-DNJ indicating that gp120 expressed in treated cells carries immature, high mannose type oligosaccharides. In addition, using metabolic labeling with [3H]mannose, gel filtration chromatography, and digestion with highly purified glucosidases I and 11, we provide the first definitive evidence that glucosidase I inhibition occurs at the anti-viral concentration of NB-DNJ. These data indicate that glucosidase inhibition is a candidate mechanism for the anti-viral activity of this compound. The biosynthesis of N-linked oligosaccharides involves the cotranslational transfer of a GlcsMan9GlcNAc2 precursor from a dolichol carrier onto the asparagine residue of an Asn-X-Ser/Thr glycosylation sequon of the protein. Terminal glucose residues are rapidly cleaved by ER-located' a-glucosidases of which two distinct activities have been identified * The Glycobiology Institute is supported by the Monsanto/Searle Co. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. $ Supported by The Swedish National Board for Technical Development (NUTEK) and a Glycobiology Institute Research schoIarship. 11 To whom correspondence should be addressed. 'The abbreviations used are: ER, endoplasmic reticulum; HIV, human immunodeficiency virus; NB-DNJ, N-butyldeoxynojirimycin; PAGE, polyacrylamide gel electrophoresis; CHO, Chinese hamster ovary; FCS, fetal calf serum; mAb, monoclonal antibody; TLCK, N"p-tosyl-L-lysine chloromethyl ketone hydrochloride; TPCK, N-tosyl-L-phenylalanine chloromethyl ketone; PBS, phosphate-buffered saline; endo, endoglycosidase; g u , glucose unit(s).