The Experts below are selected from a list of 426 Experts worldwide ranked by ideXlab platform
Frances M. Platt - One of the best experts on this subject based on the ideXlab platform.
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Accumulation of Glucosylceramide in Murine Testis, Caused by Inhibition of -Glucosidase 2 IMPLICATIONS FOR SPERMATOGENESIS*□S
2016Co-Authors: Frances M. Platt, Aarnoud C Van Der SpoelAbstract:One of the hallmarks of male germ cell development is the formation of a specialized secretory organelle, the acrosome. This process can be pharmacologically disturbed in C57BL/6 mice, and thus infertility can be induced, by small molecular sugar-like compounds (alkylated Imino Sugars). Here the bio-chemical basis of this effect has been investigated. Our findings suggest that in vivo alkylated Imino Sugars primarily interact with the non-lysosomal glucosylceramidase. This enzyme cleaves glucosylceramide into glucose and ceramide, is sensitive to Imino Sugars in vitro, and has been characterized as -gluco-sidase 2 (GBA2). Imino Sugars raised the level of glucosylcera-mide in brain, spleen, and testis, in a dose-dependent fashion. In testis, multiple species of glucosylceramide were similarly ele-vated, those having long acyl chains (C16–24), as well as those with very long polyunsaturated acyl chains (C28–30:5). Both o
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1568-0266/03 $41.00+.00 © 2003 Bentham Science Publishers Ltd. Therapeutic Applications of Imino Sugars in Lysosomal Storage Disorders
2016Co-Authors: Terry D. Butters, Raymond A. Dwek, Frances M. PlattAbstract:Abstract: The N-alkylated Imino Sugars have inhibitory activity against the first enzyme in the pathway for glucosylating sphingolipid in eukaryotic cells, ceramide-specific glucosyltransferase. A therapeutic approach termed ‘substrate deprivation ’ or ‘substrate reduction therapy ’ (SRT) aims to reduce biosynthetic capability in the cell to match the reduced lysosomal catalytic activity seen in lysosomal storage disorders. The use of N-alkylated Imino Sugars to establish this therapeutic strategy is described in cell culture and gene knockout mouse disease models. One Imino sugar, N-butyl-DNJ (NB-DNJ) has been in clinical trials for type 1 Gaucher disease and has shown to be an effective therapy for this disorder. Key Words: lysosomal, glycosidase, glucosyltransferase, glycolipid, inhibitor, substrate reduction therapy
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beneficial effects of substrate reduction therapy in a mouse model of gm1 gangliosidosis
Molecular Genetics and Metabolism, 2008Co-Authors: Elena Elliotsmith, Mylvaganam Jeyakumar, Aarnoud C Van Der Spoel, Emyr Lloydevans, Terry D. Butters, Anneliese O Speak, Raymond A. Dwek, Alessandra Dazzo, David Smith, Frances M. PlattAbstract:Abstract GM1 gangliosidosis is an inherited neurodegenerative disorder caused by lysosomal β-galactosidase deficiency, resulting in the storage of GM1 and GA1, primarily in the central nervous system. This disease typically afflicts infants and young children and there is currently no effective therapy. Substrate reduction therapy (SRT) could be of potential benefit. The Imino Sugars N -butyldeoxynojirimycin ( N B-DNJ, miglustat, Zavesca™) and N -butyldeoxygalactonojirimycin ( N B-DGJ) used for SRT inhibit glucosylceramide synthase (GlcCerS) that catalyses the first committed step in glycosphingolipid biosynthesis. We have compared the efficacy and tolerability of N B-DNJ and N B-DGJ in the β-galactosidase knockout mouse. N B-DGJ was better tolerated than N B-DNJ, due to intrinsic gastrointestinal tract dysfunction that was exacerbated by N B-DNJ. However, functional improvement was greatest with N B-DNJ treatment which may potentially be caused by novel anti-inflammatory properties of N B-DNJ.
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beneficial effects of substrate reduction therapy in a mouse model of gm1 gangliosidosis
Molecular Genetics and Metabolism, 2008Co-Authors: Elena Elliotsmith, Mylvaganam Jeyakumar, Emyr Lloydevans, Terry D. Butters, Anneliese O Speak, Raymond A. Dwek, Alessandra Dazzo, David Smith, Aarnoud C Van Der Spoel, Frances M. PlattAbstract:GM1 gangliosidosis is an inherited neurodegenerative disorder caused by lysosomal beta-galactosidase deficiency, resulting in the storage of GM1 and GA1, primarily in the central nervous system. This disease typically afflicts infants and young children and there is currently no effective therapy. Substrate reduction therapy (SRT) could be of potential benefit. The Imino Sugars N-butyldeoxynojirimycin (NB-DNJ, miglustat, Zavesca) and N-butyldeoxygalactonojirimycin (NB-DGJ) used for SRT inhibit glucosylceramide synthase (GlcCerS) that catalyses the first committed step in glycosphingolipid biosynthesis. We have compared the efficacy and tolerability of NB-DNJ and NB-DGJ in the beta-galactosidase knockout mouse. NB-DGJ was better tolerated than NB-DNJ, due to intrinsic gastrointestinal tract dysfunction that was exacerbated by NB-DNJ. However, functional improvement was greatest with NB-DNJ treatment which may potentially be caused by novel anti-inflammatory properties of NB-DNJ.
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the postacrosomal assembly of sperm head protein pawp is independent of acrosome formation and dependent on microtubular manchette transport
Developmental Biology, 2007Co-Authors: Peter Sutovsky, Frances M. Platt, Aarnoud C Van Der Spoel, Richard OkoAbstract:PAWP (postacrosomal sheath WW domain-binding protein) exclusively resides in the postacrosomal sheath (PAS) of the sperm perinuclear theca (PT). Because of the importance of this region in initiating oocyte activation during mammalian fertilization [Sutovsky, P., Manandhar, G., Wu, A., Oko, R., 2003. Interactions of sperm perinuclear theca with the oocyte: implications for oocyte activation, anti-polyspermy defense, and assisted reproduction. Microsc. Res. Tech. 61, 362–378; Wu, A., Sutovsky, P., Manandhar, G., Xu, W., Katayama, M., Day, B.N., Park, K.W., Yi, Y.J., Xi, Y.W., Prather, R.S., Oko, R., 2007. PAWP, A sperm specific ww-domain binding protein, promotes meiotic resumption and pronuclear development during fertilization. J. Biol. Chem. 282, 12164–12175], we were interested in resolving the origin and assembly of its proteins during spermatogenesis, utilizing PAWP as a model. Based on previous PT developmental studies, we predicted that the assembly of PAWP is dependent on microtubule-manchette protein transport and manchette descent and independent of subacrosomal PT formation. Consequently, we hypothesized that PAWP will colocalize with manchette microtubules during spermiogenesis. Utilizing specific antibodies, PAWP was first detected in the cytoplasmic lobe of spermatids beginning to undergo elongation and became most prominent in this region just prior to and during manchette descent. During this peak period, PAWP was concentrated over the manchette and colocalized with alpha- and beta-tubulin. It was then assembled as part of the PAS in the wake of manchette descent over the caudal half of the elongated spermatid nucleus. PAWP mRNA, on the other hand, was first detected in mid-pachytene spermatocytes, peaked by early round spermatids, and declined during spermatid elongation. In order to confirm that PAWP-PAS assembly was independent of subacrosomal PT development, PAWP immunolocalization was performed on the testes of NB-DNJ-treated mice which fail to form an acrosome and subacrosomal layer during spermiogenesis [van der Spoel, A.C., Jeyakumar, M., Butters, T.D., Charlton, H.M., Moore, H.D., Dwek, R.A., Platt, F.M., 2002. Reversible infertility in male mice after oral administration of alkylated Imino Sugars: a nonhormonal approach to male contraception. Proc. Natl. Acad. Sci. U.S.A. 99, 17173–17178] but whose elongated spermatids still retain egg-activating ability [Suganuma, R., Walden, C.M., Butters, T.D., Platt, F.M., Dwek, R.A., Yanagimachi, R., and van der Spoel, A.C., 2005. Alkylated Imino Sugars, reversible male infertility-inducing agents, do not affect the genetic integrity of male mouse germ cells during short-term treatment despite induction of sperm deformities. Biol. Reprod. 72, 805–813]. The same temporal and manchette-based pattern of PAWP-PAS assembly during spermiogenesis was evident as in controls supporting our hypothesis that PAS assembly is independent of subacrosomal PT formation and that egg-activating ability resides within the PAS.
Terry D. Butters - One of the best experts on this subject based on the ideXlab platform.
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but Does Not Affect N-Linked Oligosaccharide Processing*
2016Co-Authors: Frances M. Platts, Raymond A. Dwek, Gabrielle R. Neisesp, Gunilla B. Karlsson, Terry D. ButtersAbstract:We have previously reported that the Imino sugar N-butyldeoxynojirimycin (NB-DNJ) inhibits glycolipid biosynthesis, in addition to its known activity as an in-hibitor of the N-linked oligosaccharide processing en-zyme a-glucosidase I. In an attempt to dissociate these two activities and identify an inhibitor which was more selective for the glycolipid biosynthetic pathway, sev-eral Imino Sugars have been N-alkylated and tested for inhibitory activity. The galactose analogue N-butyldeoxygalactonojirimy-cin (NB-DGJ) was found to be a potent inhibitor of gly-colipid biosynthesis but in contrast to NB-DNJ had no effect on the maturation of N-linked oligosaccharides or on lysosomal glucocerebrosidase. The effect of increasing N-alkyl chain length on gly
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Preparation, biochemical characterization and biological properties
2016Co-Authors: George W. J. Fleet, Terry D. ButtersAbstract:We have reductively alkylated deoxynojirimycin Imino Sugars using sodium cyanoborohydride to provide an efficient means of generating a series of N-alkylated compounds containing 4–18 carbon side chains. The yields were greater than 90 % using a variety of aldehydes of different chain lengths, and after puri-fication were " 95 % pure using "H-NMR. Radiolabelled compounds were prepared using sodium cyanoborotriti-ide to selectively label the first carbon atom in the alkyl chain andused in protein-binding and cell- and tissue-uptake experiments. Protein binding was chain-length-dependent with compounds of inter-mediate chain length (
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1568-0266/03 $41.00+.00 © 2003 Bentham Science Publishers Ltd. Therapeutic Applications of Imino Sugars in Lysosomal Storage Disorders
2016Co-Authors: Terry D. Butters, Raymond A. Dwek, Frances M. PlattAbstract:Abstract: The N-alkylated Imino Sugars have inhibitory activity against the first enzyme in the pathway for glucosylating sphingolipid in eukaryotic cells, ceramide-specific glucosyltransferase. A therapeutic approach termed ‘substrate deprivation ’ or ‘substrate reduction therapy ’ (SRT) aims to reduce biosynthetic capability in the cell to match the reduced lysosomal catalytic activity seen in lysosomal storage disorders. The use of N-alkylated Imino Sugars to establish this therapeutic strategy is described in cell culture and gene knockout mouse disease models. One Imino sugar, N-butyl-DNJ (NB-DNJ) has been in clinical trials for type 1 Gaucher disease and has shown to be an effective therapy for this disorder. Key Words: lysosomal, glycosidase, glucosyltransferase, glycolipid, inhibitor, substrate reduction therapy
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inhibitors of endoplasmic reticulum α glucosidases potently suppress hepatitis c virus virion assembly and release
Antimicrobial Agents and Chemotherapy, 2011Co-Authors: Xiaoben Pan, Terry D. Butters, Dominic S. Alonzi, Jessica M Weidner, Timothy M Block, Jutao Guo, Jinhong ChangAbstract:ABSTRACT α-Glucosidases I and II are endoplasmic reticulum-resident enzymes that are essential for N-linked glycan processing and subsequent proper folding of glycoproteins. In this report, we first demonstrate that downregulation of the expression of α-glucosidase I, II, or both in Huh7.5 cells by small hairpin RNA technology inhibited the production of hepatitis C virus (HCV). In agreement with the essential role of α-glucosidases in HCV envelope glycoprotein processing and folding, treatment of HCV-infected cells with a panel of Imino sugar derivatives, which are competitive inhibitors of α-glucosidases, did not affect intracellular HCV RNA replication and nonstructural protein expression but resulted in the inhibition of glycan processing and subsequent degradation of HCV E2 glycoprotein. As a consequence, HCV virion assembly and secretion were inhibited. In searching for Imino Sugars with better antiviral activity, we found that a novel Imino sugar, PBDNJ0804, had a superior ability to inhibit HCV virion assembly and secretion. In summary, we demonstrated that glucosidases are important host factor-based antiviral targets for HCV infection. The low likelihood of drug-resistant virus emergence and potent antiviral efficacy of the novel glucosidase inhibitor hold promise for its development as a therapeutic agent for the treatment of chronic hepatitis C.
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Lysosomal storage of oligosaccharide and glycosphingolipid in Imino sugar treated cells
Glycoconjugate Journal, 2010Co-Authors: Stephanie D. Boomkamp, James Samuel Shane Rountree, David C. A. Neville, Raymond A. Dwek, George W. J. Fleet, Terry D. ButtersAbstract:Sandhoff and Tay-Sachs disease are autosomal recessive GM2 gangliosidoses where a deficiency of lysosomal β-hexosaminidase results in storage of glycoconjugates. Imino sugar (2-acetamido-1,4-Imino-1,2,4-trideoxy-L-arabinitol) inhibition of β-hexosaminidase in murine RAW264.7 macrophage-like cells led to lysosomal storage of glycoconjugates that were characterised structurally using fluorescence labelling of the free or glycolipid-derived oligosaccharides followed by HPLC and mass spectrometry. Stored glycoconjugates were confirmed as containing non-reducing GlcNAc or GalNAc residues resulting from the incomplete degradation of N-linked glycoprotein oligosaccharide and glycolipids, respectively. When substrate reduction therapeutics N -butyl-deoxynojirimycin ( N B-DNJ) or N -butyldeoxygalactonojirimycin ( N B-DGJ) were applied to the storage phenotype cells, an increase in glucosylated and galactosylated oligosaccharide species was observed due to endoplasmic reticulum α-glucosidases and lysosomal β-galactosidase inhibition, respectively. Hexosaminidase inhibition triggered a tightly regulated cytokine-mediated inflammatory response that was normalised using Imino Sugars N B-DNJ and N B-DGJ, which restored the GM2 ganglioside storage burden but failed to reduce the levels of GA2 glycolipid or glycoprotein-derived N -linked oligosaccharides. Using a chemically induced gangliosidosis phenotype that can be modulated with substrate lowering drugs, the critical role of GM2 ganglioside in the progression of inflammatory disease is also demonstrated.
Raymond A. Dwek - One of the best experts on this subject based on the ideXlab platform.
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but Does Not Affect N-Linked Oligosaccharide Processing*
2016Co-Authors: Frances M. Platts, Raymond A. Dwek, Gabrielle R. Neisesp, Gunilla B. Karlsson, Terry D. ButtersAbstract:We have previously reported that the Imino sugar N-butyldeoxynojirimycin (NB-DNJ) inhibits glycolipid biosynthesis, in addition to its known activity as an in-hibitor of the N-linked oligosaccharide processing en-zyme a-glucosidase I. In an attempt to dissociate these two activities and identify an inhibitor which was more selective for the glycolipid biosynthetic pathway, sev-eral Imino Sugars have been N-alkylated and tested for inhibitory activity. The galactose analogue N-butyldeoxygalactonojirimy-cin (NB-DGJ) was found to be a potent inhibitor of gly-colipid biosynthesis but in contrast to NB-DNJ had no effect on the maturation of N-linked oligosaccharides or on lysosomal glucocerebrosidase. The effect of increasing N-alkyl chain length on gly
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1568-0266/03 $41.00+.00 © 2003 Bentham Science Publishers Ltd. Therapeutic Applications of Imino Sugars in Lysosomal Storage Disorders
2016Co-Authors: Terry D. Butters, Raymond A. Dwek, Frances M. PlattAbstract:Abstract: The N-alkylated Imino Sugars have inhibitory activity against the first enzyme in the pathway for glucosylating sphingolipid in eukaryotic cells, ceramide-specific glucosyltransferase. A therapeutic approach termed ‘substrate deprivation ’ or ‘substrate reduction therapy ’ (SRT) aims to reduce biosynthetic capability in the cell to match the reduced lysosomal catalytic activity seen in lysosomal storage disorders. The use of N-alkylated Imino Sugars to establish this therapeutic strategy is described in cell culture and gene knockout mouse disease models. One Imino sugar, N-butyl-DNJ (NB-DNJ) has been in clinical trials for type 1 Gaucher disease and has shown to be an effective therapy for this disorder. Key Words: lysosomal, glycosidase, glucosyltransferase, glycolipid, inhibitor, substrate reduction therapy
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Lysosomal storage of oligosaccharide and glycosphingolipid in Imino sugar treated cells
Glycoconjugate Journal, 2010Co-Authors: Stephanie D. Boomkamp, James Samuel Shane Rountree, David C. A. Neville, Raymond A. Dwek, George W. J. Fleet, Terry D. ButtersAbstract:Sandhoff and Tay-Sachs disease are autosomal recessive GM2 gangliosidoses where a deficiency of lysosomal β-hexosaminidase results in storage of glycoconjugates. Imino sugar (2-acetamido-1,4-Imino-1,2,4-trideoxy-L-arabinitol) inhibition of β-hexosaminidase in murine RAW264.7 macrophage-like cells led to lysosomal storage of glycoconjugates that were characterised structurally using fluorescence labelling of the free or glycolipid-derived oligosaccharides followed by HPLC and mass spectrometry. Stored glycoconjugates were confirmed as containing non-reducing GlcNAc or GalNAc residues resulting from the incomplete degradation of N-linked glycoprotein oligosaccharide and glycolipids, respectively. When substrate reduction therapeutics N -butyl-deoxynojirimycin ( N B-DNJ) or N -butyldeoxygalactonojirimycin ( N B-DGJ) were applied to the storage phenotype cells, an increase in glucosylated and galactosylated oligosaccharide species was observed due to endoplasmic reticulum α-glucosidases and lysosomal β-galactosidase inhibition, respectively. Hexosaminidase inhibition triggered a tightly regulated cytokine-mediated inflammatory response that was normalised using Imino Sugars N B-DNJ and N B-DGJ, which restored the GM2 ganglioside storage burden but failed to reduce the levels of GA2 glycolipid or glycoprotein-derived N -linked oligosaccharides. Using a chemically induced gangliosidosis phenotype that can be modulated with substrate lowering drugs, the critical role of GM2 ganglioside in the progression of inflammatory disease is also demonstrated.
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Lysosomal storage of oligosaccharide and glycosphingolipid in Imino sugar treated cells.
'Springer Science and Business Media LLC', 2010Co-Authors: Stephanie D. Boomkamp, Raymond A. Dwek, Dc Neville, Js Rountree, Gw Fleet, Td ButtersAbstract:Sandhoff and Tay-Sachs disease are autosomal recessive GM2 gangliosidoses where a deficiency of lysosomal beta-hexosaminidase results in storage of glycoconjugates. Imino sugar (2-acetamido-1,4-Imino-1,2,4-trideoxy-L-arabinitol) inhibition of beta-hexosaminidase in murine RAW264.7 macrophage-like cells led to lysosomal storage of glycoconjugates that were characterised structurally using fluorescence labelling of the free or glycolipid-derived oligosaccharides followed by HPLC and mass spectrometry. Stored glycoconjugates were confirmed as containing non-reducing GlcNAc or GalNAc residues resulting from the incomplete degradation of N-linked glycoprotein oligosaccharide and glycolipids, respectively. When substrate reduction therapeutics N-butyl-deoxynojirimycin (NB-DNJ) or N-butyldeoxygalactonojirimycin (NB-DGJ) were applied to the storage phenotype cells, an increase in glucosylated and galactosylated oligosaccharide species was observed due to endoplasmic reticulum alpha-glucosidases and lysosomal beta-galactosidase inhibition, respectively. Hexosaminidase inhibition triggered a tightly regulated cytokine-mediated inflammatory response that was normalised using Imino Sugars NB-DNJ and NB-DGJ, which restored the GM2 ganglioside storage burden but failed to reduce the levels of GA2 glycolipid or glycoprotein-derived N-linked oligosaccharides. Using a chemically induced gangliosidosis phenotype that can be modulated with substrate lowering drugs, the critical role of GM2 ganglioside in the progression of inflammatory disease is also demonstrated
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beneficial effects of substrate reduction therapy in a mouse model of gm1 gangliosidosis
Molecular Genetics and Metabolism, 2008Co-Authors: Elena Elliotsmith, Mylvaganam Jeyakumar, Aarnoud C Van Der Spoel, Emyr Lloydevans, Terry D. Butters, Anneliese O Speak, Raymond A. Dwek, Alessandra Dazzo, David Smith, Frances M. PlattAbstract:Abstract GM1 gangliosidosis is an inherited neurodegenerative disorder caused by lysosomal β-galactosidase deficiency, resulting in the storage of GM1 and GA1, primarily in the central nervous system. This disease typically afflicts infants and young children and there is currently no effective therapy. Substrate reduction therapy (SRT) could be of potential benefit. The Imino Sugars N -butyldeoxynojirimycin ( N B-DNJ, miglustat, Zavesca™) and N -butyldeoxygalactonojirimycin ( N B-DGJ) used for SRT inhibit glucosylceramide synthase (GlcCerS) that catalyses the first committed step in glycosphingolipid biosynthesis. We have compared the efficacy and tolerability of N B-DNJ and N B-DGJ in the β-galactosidase knockout mouse. N B-DGJ was better tolerated than N B-DNJ, due to intrinsic gastrointestinal tract dysfunction that was exacerbated by N B-DNJ. However, functional improvement was greatest with N B-DNJ treatment which may potentially be caused by novel anti-inflammatory properties of N B-DNJ.
Timothy M Block - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of Hepatitis B Virus DNA Replication by Imino Sugars Without the Inhibition of the DNA Polymerase: Therapeutic Implications
2016Co-Authors: Timothy M BlockAbstract:Previously we have shown that the Imino sugar inhibitor of N-linked glycan processing, N-nonyl-deoxynojirimycin (N-nonyl-DNJ), had antiviral activity in the woodchuck model of chronic hepatitis B virus (HBV) infection. In study-ing the mechanism of action of this compound, it was discovered that Imino Sugars could inhibit HBV secretion without inhibiting N-linked glycoprocessing. Although N-nonyl-DNJ is an inhibitor of the endoplasmic reticulum (ER) glucosidase, here it is shown that N-nonyl-DNJ retained an-tiviral activity at concentrations that had no significant impact on ER glucosidase function. Taken together, these results suggested that N-nonyl-DNJ possessed an antivi-ral activity attributable to a function other than an impact on glycoprocessing. This hypothesis was confirmed by experiments showing that N-nonyl-deoxygalactojirimyci
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inhibitors of endoplasmic reticulum α glucosidases potently suppress hepatitis c virus virion assembly and release
Antimicrobial Agents and Chemotherapy, 2011Co-Authors: Xiaoben Pan, Terry D. Butters, Dominic S. Alonzi, Jessica M Weidner, Timothy M Block, Jutao Guo, Jinhong ChangAbstract:ABSTRACT α-Glucosidases I and II are endoplasmic reticulum-resident enzymes that are essential for N-linked glycan processing and subsequent proper folding of glycoproteins. In this report, we first demonstrate that downregulation of the expression of α-glucosidase I, II, or both in Huh7.5 cells by small hairpin RNA technology inhibited the production of hepatitis C virus (HCV). In agreement with the essential role of α-glucosidases in HCV envelope glycoprotein processing and folding, treatment of HCV-infected cells with a panel of Imino sugar derivatives, which are competitive inhibitors of α-glucosidases, did not affect intracellular HCV RNA replication and nonstructural protein expression but resulted in the inhibition of glycan processing and subsequent degradation of HCV E2 glycoprotein. As a consequence, HCV virion assembly and secretion were inhibited. In searching for Imino Sugars with better antiviral activity, we found that a novel Imino sugar, PBDNJ0804, had a superior ability to inhibit HCV virion assembly and secretion. In summary, we demonstrated that glucosidases are important host factor-based antiviral targets for HCV infection. The low likelihood of drug-resistant virus emergence and potent antiviral efficacy of the novel glucosidase inhibitor hold promise for its development as a therapeutic agent for the treatment of chronic hepatitis C.
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novel Imino sugar derivatives demonstrate potent antiviral activity against flaviviruses
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: Jinhong Chang, Jutao Guo, Lijuan Wang, Haitao Guo, Peter M Mason, Nigel Bourne, Robert M Moriarty, Timothy M BlockAbstract:Imino Sugars, such as N-butyl-deoxynojirimycin and N-nonyl-deoxynojirimycin (NNDNJ), are glucose analogues that selectively inhibit cellular alpha-glucosidase I and II in the endoplasmic reticulum and exhibit antiviral activities against many types of enveloped viruses. Although these molecules have broad-spectrum antiviral activity, their development has been limited by a lack of efficacy and/or selectivity. We have previously reported that a DNJ derivative with a hydroxylated cyclohexyl side chain, called OSL-95II, has an antiviral efficacy similar to that of NNDNJ but significantly less toxicity. Building upon this observation, a family of Imino sugar derivatives containing an oxygenated side chain and terminally restricted ring structures were synthesized and shown to have low cytotoxicity and superior antiviral activity against members of the Flaviviridae family, including bovine viral diarrhea virus, dengue virus (DENV), and West Nile virus. Of particular interest is that several of these novel Imino sugar derivatives, such as PBDNJ0801, PBDNJ0803, and PBDNJ0804, potently inhibit DENV infection in vitro, with 90% effective concentration values at submicromolar concentrations and selectivity indices greater than 800. Therefore, these compounds represent the best in their class and may offer realistic candidates for the development of antiviral therapeutics against human DENV infections.
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Imino Sugars inhibit the formation and secretion of bovine viral diarrhea virus a pestivirus model of hepatitis c virus implications for the development of broad spectrum anti hepatitis virus agents
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Nicole Zitzmann, Terry D. Butters, Raymond A. Dwek, Frances M. Platt, Anand Mehta, Sandra Carrouee, John W Mccauley, Baruch S Blumberg, Timothy M BlockAbstract:One function of N-linked glycans is to assist in the folding of glycoproteins by mediating interactions of the lectin-like chaperone proteins calnexin and calreticulin with nascent glycoproteins. These interactions can be prevented by inhibitors of the α-glucosidases, such as N-butyl-deoxynojirimycin (NB-DNJ) and N-nonyl-DNJ (NN-DNJ), and this causes some proteins to be misfolded and retained within the endoplasmic reticulum (ER). We have shown previously that the NN-DNJ-induced misfolding of one of the hepatitis B virus (HBV) envelope glycoproteins prevents the formation and secretion of virus in vitro and that this inhibitor alters glycosylation and reduces the viral levels in an animal model of chronic HBV infection. This led us to investigate the effect of glucosidase inhibitors on another ER-budding virus, bovine viral diarrhea virus, a tissue culture surrogate of human hepatitis C virus (HCV). Here we show that in MDBK cells α-glucosidase inhibitors prevented the formation and secretion of infectious bovine viral diarrhea virus. Data also are presented showing that NN-DNJ, compared with NB-DNJ, exhibits a prolonged retention in liver in vivo. Because viral secretion is selectively hypersensitive to glucosidase inhibition relative to the secretion of cellular proteins, the possibility that glucosidase inhibitors could be used as broad-based antiviral hepatitis agents is discussed. A single drug against HBV, HCV, and, possibly, HDV, which together chronically infect more than 400 million people worldwide, would be of great therapeutic value.
Jinhong Chang - One of the best experts on this subject based on the ideXlab platform.
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small molecule inhibitors of er α glucosidases are active against multiple hemorrhagic fever viruses
Antiviral Research, 2013Co-Authors: Jinhong Chang, Dominic S. Alonzi, Lijuan Wang, Travis K Warren, Xuesen Zhao, Tina Gill, Fang Guo, Mary Ann Comunale, Fei Liu, Jutao GuoAbstract:Host cellular endoplasmic reticulum α-glucosidases I and II are essential for the maturation of viral glycosylated envelope proteins that use the calnexin mediated folding pathway. Inhibition of these glycan processing enzymes leads to the misfolding and degradation of these viral glycoproteins and subsequent reduction in virion secretion. We previously reported that, CM-10-18, an Imino sugar α-glucosidase inhibitor, efficiently protected the lethality of dengue virus infection of mice. In the current study, through an extensive structure-activity relationship study, we have identified three CM-10-18 derivatives that demonstrated superior in vitro antiviral activity against representative viruses from four viral families causing hemorrhagic fever. Moreover, the three novel Imino Sugars significantly reduced the mortality of two of the most pathogenic hemorrhagic fever viruses, Marburg virus and Ebola virus, in mice. Our study thus proves the concept that Imino Sugars are promising drug candidates for the management of viral hemorrhagic fever caused by variety of viruses.
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inhibitors of endoplasmic reticulum α glucosidases potently suppress hepatitis c virus virion assembly and release
Antimicrobial Agents and Chemotherapy, 2011Co-Authors: Xiaoben Pan, Terry D. Butters, Dominic S. Alonzi, Jessica M Weidner, Timothy M Block, Jutao Guo, Jinhong ChangAbstract:ABSTRACT α-Glucosidases I and II are endoplasmic reticulum-resident enzymes that are essential for N-linked glycan processing and subsequent proper folding of glycoproteins. In this report, we first demonstrate that downregulation of the expression of α-glucosidase I, II, or both in Huh7.5 cells by small hairpin RNA technology inhibited the production of hepatitis C virus (HCV). In agreement with the essential role of α-glucosidases in HCV envelope glycoprotein processing and folding, treatment of HCV-infected cells with a panel of Imino sugar derivatives, which are competitive inhibitors of α-glucosidases, did not affect intracellular HCV RNA replication and nonstructural protein expression but resulted in the inhibition of glycan processing and subsequent degradation of HCV E2 glycoprotein. As a consequence, HCV virion assembly and secretion were inhibited. In searching for Imino Sugars with better antiviral activity, we found that a novel Imino sugar, PBDNJ0804, had a superior ability to inhibit HCV virion assembly and secretion. In summary, we demonstrated that glucosidases are important host factor-based antiviral targets for HCV infection. The low likelihood of drug-resistant virus emergence and potent antiviral efficacy of the novel glucosidase inhibitor hold promise for its development as a therapeutic agent for the treatment of chronic hepatitis C.
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Inhibitors of Endoplasmic Reticulum -Glucosidases Potently Suppress Hepatitis C Virus Virion Assembly and Release
2010Co-Authors: Terry Butters, Jutao Guo, Timothy Block, Jinhong ChangAbstract:-Glucosidases I and II are endoplasmic reticulum-resident enzymes that are essential for N-linked glycan processing and subsequent proper folding of glycoproteins. In this report, we first demonstrate that down-regulation of the expression of -glucosidase I, II, or both in Huh7.5 cells by small hairpin RNA technology inhibited the production of hepatitis C virus (HCV). In agreement with the essential role of -glucosidases in HCV envelope glycoprotein processing and folding, treatment of HCV-infected cells with a panel of Imino sugar derivatives, which are competitive inhibitors of -glucosidases, did not affect intracellular HCV RNA replica-tion and nonstructural protein expression but resulted in the inhibition of glycan processing and subsequent degradation of HCV E2 glycoprotein. As a consequence, HCV virion assembly and secretion were inhibited. In searching for Imino Sugars with better antiviral activity, we found that a novel Imino sugar, PBDNJ0804, had a superior ability to inhibit HCV virion assembly and secretion. In summary, we demonstrated that glucosi-dases are important host factor-based antiviral targets for HCV infection. The low likelihood of drug-resistant virus emergence and potent antiviral efficacy of the novel glucosidase inhibitor hold promise for its develop-ment as a therapeutic agent for the treatment of chronic hepatitis C. Hepatitis C virus (HCV) chronically infects more than 170 million people worldwide. Current standard therapy for chroni
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novel Imino sugar derivatives demonstrate potent antiviral activity against flaviviruses
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: Jinhong Chang, Jutao Guo, Lijuan Wang, Haitao Guo, Peter M Mason, Nigel Bourne, Robert M Moriarty, Timothy M BlockAbstract:Imino Sugars, such as N-butyl-deoxynojirimycin and N-nonyl-deoxynojirimycin (NNDNJ), are glucose analogues that selectively inhibit cellular alpha-glucosidase I and II in the endoplasmic reticulum and exhibit antiviral activities against many types of enveloped viruses. Although these molecules have broad-spectrum antiviral activity, their development has been limited by a lack of efficacy and/or selectivity. We have previously reported that a DNJ derivative with a hydroxylated cyclohexyl side chain, called OSL-95II, has an antiviral efficacy similar to that of NNDNJ but significantly less toxicity. Building upon this observation, a family of Imino sugar derivatives containing an oxygenated side chain and terminally restricted ring structures were synthesized and shown to have low cytotoxicity and superior antiviral activity against members of the Flaviviridae family, including bovine viral diarrhea virus, dengue virus (DENV), and West Nile virus. Of particular interest is that several of these novel Imino sugar derivatives, such as PBDNJ0801, PBDNJ0803, and PBDNJ0804, potently inhibit DENV infection in vitro, with 90% effective concentration values at submicromolar concentrations and selectivity indices greater than 800. Therefore, these compounds represent the best in their class and may offer realistic candidates for the development of antiviral therapeutics against human DENV infections.
