Design and Screening Strategies for &amp;#945;-Glucosidase Inhibitors Based on Enzymological Information

Hakamata, Wataru; Kurihara, Masaaki; Okuda, Haruhiro; Nishio, Takeshi; Oku, Tatsuo

doi:10.2174/156802609787354306

Cited by 84 publications

(60 citation statements)

References 72 publications

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“…In fact, this approach has been explored by others for the identification of gut maltase-specific inhibitors for the treatment of diabetes (Hakamata et al, 2012). Development of a convenient fluorescent substrate-based in vitro enzymatic assay for ER a-glucosidases will be the first step towards discovery of novel allosteric inhibitors, which may ultimately improve ER a-glucosidase-targeted antiviral therapy (Hakamata et al, 2009).…”

Section: Approaches Toward Improved Er-alpha Glucosidase-targeted Antmentioning

confidence: 99%

Antiviral therapies targeting host ER alpha-glucosidases: Current status and future directions

2013

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Endoplasmic reticulum (ER)-resident α-glucosidases I and II sequentially trim the three terminal glucose moieties on N-linked glycans attached to nascent glycoproteins. These reactions are the first steps of N-linked glycan processing and are essential for proper folding and function of many glycoproteins. Because most viral envelope glycoproteins contain N-linked glycans, inhibition of ER α-glucosidases with derivatives of 1-deoxynojirimycin (DNJ) or castanospermine (CAST), two well-studied pharmacophores of α-glucosidase inhibitors, efficiently disrupts the morphogenesis of a broad spectrum of enveloped viruses. Moreover, both DNJ and CAST derivatives have been demonstrated to prevent the death of mice infected with several distinct flaviviruses and filoviruses and suppress the multiplication of several other species of viruses in infected animals. N-Butyl derivative of DNJ (NB-DNJ) and 6 O-bytanoyl prodrug of CAST (Bu-CAST) have been evaluated in human clinical trials for their antiviral activities against human immunodeficiency virus and hepatitis C virus, and there is an ongoing trial of treating dengue patients with Bu-CAST. This article summarizes the current status of ER α-glucosidase-targeted antiviral therapy and proposes strategies for development of more efficacious and specific ER α-glucosidase inhibitors as broad-spectrum, drug resistance-refractory antiviral therapeutics. These host function-targeted, broad-spectrum antiviral agents do not rely on time-consuming etiologic diagnosis, and should therefore be particularly promising in the management of viral hemorrhagic fever and respiratory tract viral infections, medical conditions that can be caused by many different enveloped RNA viruses, with a short window for medical intervention.

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Section: Approaches Toward Improved Er-alpha Glucosidase-targeted Antmentioning

confidence: 99%

Antiviral therapies targeting host ER alpha-glucosidases: Current status and future directions

2013

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“…86,87 Some of them have been successfully used to treat human diseases. 82,83 For example, inhibition of intestinal glucosidases digesting carbohydrates is therapeutic for the management of type II diabetes.…”

Section: Current Uses and Limitations Of Glucosidase Inhibitorsmentioning

confidence: 99%

Imino sugar glucosidase inhibitors as broadly active anti-filovirus agents

Chang

Guo

et al. 2013

Emerging Microbes & Infections

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Ebola virus and Marburg virus are members of the family of Filoviridae and are etiological agents of a deadly hemorrhagic fever disease. The clinical symptoms of Ebola and Marburg hemorrhagic fevers are difficult to distinguish and there are currently no specific antiviral therapies against either of the viruses. Therefore, a drug that is safe and effective against both would be an enormous breakthrough. We and others have shown that the folding of the glycoproteins of many enveloped viruses, including the filoviruses, is far more dependent upon the calnexin pathway of protein folding than are most host glycoproteins. Drugs that inhibit this pathway would be expected to be selectively antiviral. Indeed, as we summarize in this review, imino sugars that are competitive inhibitors of the host endoplasmic reticular α-glucosidases I and II, which are enzymes that process N-glycan on nascent glycoproteins and thereby inhibit calnexin binding to the nascent glycoproteins, have been shown to have antiviral activity against a number of enveloped viruses including filoviruses. In this review, we describe the state of development of imino sugars for use against the filoviruses, and provide an explanation for the basis of their antiviral activity as well as limitations.

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“…Generally, two approaches are employed: in vivo screening (the animal model of hyperglycemia); in vitro screening (enzyme-inhibitor model) [7][8][9][10]. The in vivo animal model provides more reliable results and is critical for the clinical assessment.…”

Section: Introductionmentioning

confidence: 99%

Sensitive colorimetric assays for α-glucosidase activity and inhibitor screening based on unmodified gold nanoparticles

Chen

Zhang

et al. 2015

Analytica Chimica Acta

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Design and Screening Strategies for α-Glucosidase Inhibitors Based on Enzymological Information

Cited by 84 publications

References 72 publications

Antiviral therapies targeting host ER alpha-glucosidases: Current status and future directions

Antiviral therapies targeting host ER alpha-glucosidases: Current status and future directions

Imino sugar glucosidase inhibitors as broadly active anti-filovirus agents

Sensitive colorimetric assays for α-glucosidase activity and inhibitor screening based on unmodified gold nanoparticles

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