Improved cellular inhibitors for glycoprotein processing α-glucosidases: biological characterisation of alkyl- and arylalkyl-N-substituted deoxynojirimycins

Alonzi, Dominic S.; Dwek, Raymond A.; Butters, Terry D.

doi:10.1016/j.tetasy.2009.03.007

Cited by 22 publications

(13 citation statements)

References 19 publications

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“…Одними из наиболее перспективных лекарственных препаратов могут стать иминосахара и их производные. Они ингибируют глюкозидазы эндоплазматической сети, приводя к нарушению фолдинга гликопротеинов вируса [51]. Большое количество исследований in vitro подтверждает выраженную противовирусную активность иминосахаров в отношении BVDV [52][53][54][55], но нет данных об экспериментах in vivo с этими соединениями.…”

Section: нарушение фолдинга гликопротеинов вирусаunclassified

“…Для ветеринарии разработан комплексный препарат, включающий рибавирин и антибактериальные препараты: триметоприм и энрофлоксацин. Он рекомендован Малые интерферирующие РНК [40,41], плазмиды, экспрессирующие shRNA [42,43] Подавление функциональной активности генов Борная кислота и ее аналоги [47,48], пиримидиновые нуклеозиды [49] Ингибирование сериновой протеазы Иминосахара и их производные [51][52][53][54][55] Нарушение фолдинга гликопротеинов вируса Амантадин [61], соединение BIT225, производное дифенилметана соединение SH-595A [63], каприлат [64] Препятствие проникновению вируса в клетку Бактериальные культуры Bacillus spp. B555, B584 и B616 [64] Ингибирование адсорбции вируса на клетку Вопросы Вирусологии.…”

Section: Introductionunclassified

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Antiviral Compounds and Preparations Effective Against Bovine Viral Diarrhea

Glotova¹,

Nikonova²,

Глотов³

2017

Problems of Virology

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Bovine viral diarrhea virus (BVDV) belongs to the genus Pestivirus, family Flaviviridae. It causes various clinical forms of infection leading to significant economic losses in beef and dairy industry worldwide. Furthermore, the virus is a contaminant of biological preparations (bovine fetal serum, continuous cell cultures, vaccines for human and veterinary medicine, interferons, trypsin, biotechnological preparations, embryos, stem cells, etc.). It is used as a test object when developing methods of decontamination. In some countries, a tool for monitoring the infection caused by the virus is vaccination based on the use of live and inactivated vaccines with varying efficiency. The antiviral compounds are a potential means of control in case of insufficient efficacy of vaccines. Their advantage for BVDV control is the ability to provide immediate protection for animals at risk in the case of an outbreak of the disease. This review summarizes the current state of knowledge about antiviral compounds against BVDV. It was noted that due to the use of advanced biomedical technologies there is a tendency to search for drugs that might be effective for antiviral therapy of BVDV, as indicated by numerous studies of new compounds and the antiviral efficacy of known drugs used in medical practice. In addition to the well-known antiviral targets for the virus, such as the RdRp, IMPDH, NS3, new targets were discovered, such as protein p7. Its mechanism of action remains to be explored. It can be concluded that there is a great potential for BVDV control through the use of antiviral drugs which has not yet implemented. The biggest obstacle for commercial implementation of identified compounds is the lack of demonstration of their efficacy in vivo. Further studies should be performed to develop a method for administering effective drugs to groups of animals.

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Section: нарушение фолдинга гликопротеинов вирусаunclassified

Section: Introductionunclassified

Antiviral Compounds and Preparations Effective Against Bovine Viral Diarrhea

Glotova¹,

Nikonova²,

Глотов³

2017

Problems of Virology

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“…NS3, which has helicase and serine protease domains, is a necessary component of the replication complex required for viral RNA replication, thus making this protein another specific target for antiviral therapy (Chaudhuri et al, 2012; Lawitz et al, 2013). Additionally, a nonspecific target of antiviral drugs is the endoplasmic reticulum (ER) glucosidases, which are essential for virion processing and packaging (Alonzi et al, 2009). Inhibition of inosine-monophosphate dehydrogenase (IMPDH) has also been targeted by in vitro studies (Stuyver et al, 2002; Buckwold et al, 2003; Yanagida et al, 2004).…”

Section: Bovine Viral Diarrhea Virusmentioning

confidence: 99%

Potential applications for antiviral therapy and prophylaxis in bovine medicine

Newcomer

Walz

Givens

2014

Anim. Health. Res. Rev.

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Viral disease is one of the major causes of financial loss and animal suffering in today's cattle industry. Increases in global commerce and average herd size, urbanization, vertical integration within the industry and alterations in global climate patterns have allowed the spread of pathogenic viruses, or the introduction of new viral species, into regions previously free of such pathogens, creating the potential for widespread morbidity and mortality in naïve cattle populations. Despite this, no antiviral products are currently commercially licensed for use in bovine medicine, although significant progress has been made in the development of antivirals for use against bovine viral diarrhea virus (BVDV), foot and mouth disease virus (FMDV) and bovine herpesvirus (BHV). BVDV is extensively studied as a model virus for human antiviral studies. Consequently, many compounds with efficacy have been identified and a few have been successfully used to prevent infection in vivo although commercial development is still lacking. FMDV is also the subject of extensive antiviral testing due to the importance of outbreak containment for maintenance of export markets. Thirdly, BHV presents an attractive target for antiviral development due to its worldwide presence. Antiviral studies for other bovine viral pathogens are largely limited to preliminary studies. This review summarizes the current state of knowledge of antiviral compounds against several key bovine pathogens and the potential for commercial antiviral applications in the prevention and control of several selected bovine diseases.

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“…Thus, to understand the relative contribution of the ring size, stereochemistry, and N -alkyl substitution on glycosidase inhibition, we proceeded with the synthesis of a small library of N -substituted 1-deoxy-L- gulo -nojirimycin and D- manno -azepane derivatives and compared them with the corresponding classical N -substituted of 1-deoxy-D- gluco -piperidine (DNJ) and L- ido -azepane counterparts as glucose-type carbohydrate mimetics. To reach this goal, N -hydroxyethyl and N -butyl groups of miglitol and miglustat drugs, respectively, were investigated as highly important N -alkyl substitutions for glucosidase inhibition, besides N -phenethyl [44], and N -propynyl [43] as a less-active counterpart.…”

Section: Introductionmentioning

confidence: 99%

Iminosugars: Effects of Stereochemistry, Ring Size, and N-Substituents on Glucosidase Activities

2019

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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 miglitol drugs. Thus, a small library of iminosugars (14 compounds) displaying different stereochemistry, ring size, and N-substitutions was successfully synthesized from a common precursor, D-mannitol, by utilizing an SN2 aminocyclization reaction via two isomeric bis-epoxides. The evaluation of the prospective inhibitors on glucosidases revealed that merely D-gluco-piperidine (miglitol, 41a) and L-ido-azepane (41b) DNJ-derivatives bearing the N-hydroxylethyl group showed inhibition towards α-glucosidase with IC50 41 µM and 138 µM, respectively, using DNJ as reference (IC50 134 µM). On the other hand, β-glucosidase inhibition was achieved for glucose-inverted configuration (C-2 and C-5) derivatives, as novel L-gulo-piperidine (27a) and D-manno-azepane (27b), preserving the N-butyl chain, with IC50 109 and 184 µM, respectively, comparable to miglustat with the same N-butyl substituent (40a, IC50 172 µM). Interestingly, the seven-membered ring L-ido-azepane (40b) displayed near twice the activity (IC50 80 µM) of the corresponding D-gluco-piperidine miglustat drug (40a). Furthermore, besides α-glucosidase inhibition, both miglitol (41a) and L-ido-azepane (41b) proved to be the strongest β-glucosidase inhibitors of the series with IC50 of 4 µM.

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Improved cellular inhibitors for glycoprotein processing α-glucosidases: biological characterisation of alkyl- and arylalkyl-N-substituted deoxynojirimycins

Cited by 22 publications

References 19 publications

Antiviral Compounds and Preparations Effective Against Bovine Viral Diarrhea

Antiviral Compounds and Preparations Effective Against Bovine Viral Diarrhea

Potential applications for antiviral therapy and prophylaxis in bovine medicine

Iminosugars: Effects of Stereochemistry, Ring Size, and N-Substituents on Glucosidase Activities

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