Virtual ligand screening of α-glucosidase: Identification of a novel potent noncarbohydrate mimetic inhibitor

Hakamata, Wataru; Ishikawa, Ryosuke; Ushijima, Yoriko; Tsukagoshi, Takumi; Tamura, Saori; Hirano, Tetsufumi; Nishio, Takeshi

doi:10.1016/j.bmcl.2011.11.084

Cited by 7 publications

(3 citation statements)

References 11 publications

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“…The most selective inhibitors of ER a-glucosidases may not be the substrate analogues targeting the catalytic center that may be similar between ER glucosidases and intestinal glucosidases, but compounds that target allosteric sites unique to ER a-glucosidases. 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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“…By contrast, structure-based virtual screening studies aim specifically to identify prospective inhibitors. However, many published virtual screening studies against carbohydrate-binding proteins have not evaluated the applied method nor used negative controls/decoys to establish retrospective enrichment. − Validation is critical for the improvement of screening methods against these targets and allows users to judge the transferability of reported successes. Where retrospective screening has been performed, enrichment indicators used include the raw number of hits returned, the ratio of retrieved actives to total actives, , 1% Enrichment Factor, and ROC AUC …”

Section: Discussionmentioning

confidence: 99%

Virtual Screening Against Carbohydrate-Binding Proteins: Evaluation and Application to Bacterial Burkholderia ambifaria Lectin

Dingjan

Gillon

Pérez

et al. 2018

J. Chem. Inf. Model.

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Bacterial adhesion to human epithelia via lectins constitutes a therapeutic opportunity to prevent infection. Specifically, BambL (the lectin from Burkholderia ambifaria) is implicated in cystic fibrosis, where lectin-mediated bacterial adhesion to fucosylated lung epithelia is suspected to play an important role. We employed structure-based virtual screening to identify inhibitors of BambL-saccharide interaction with potential therapeutic value. To enable such discovery, a virtual screening protocol was iteratively developed via 194 retrospective screening protocols against 4 bacterial lectins (BambL, BC2L-A, FimH, and LecA) with known ligands. Specific attention was given to the rigorous evaluation of retrospective screening, including calculation of analytical errors for enrichment metrics. The developed virtual screening workflow used crystallographic constraints, pharmacophore filters, and a final manual selection step. The protocol was applied to BambL, predicting 15 active compounds from virtual libraries of approximately 7 million compounds. Experimental validation using fluorescence polarization confirmed micromolar inhibitory activity for two compounds, which were further characterized by isothermal titration calorimetry and surface plasmon resonance. Subsequent testing against LecB from Pseudomonas aeruginosa demonstrated binding specificity of one of the hit compounds. This report demonstrates the utility of virtual screening protocols, integrating ligand-based pharmacophore filtering and structure-based constraints, in the search for bacterial lectin inhibitors.

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“…A promising strategy for obtaining non-substrate-mimicking ER GII inhibitors is virtual ligand screening using the X-ray crystal structure of the catalytic unit of ER GII as a template (21). Another important strategy is the screening of compound libraries, which However, there are no reports of fluorescent ER GII substrates that work with human cultured cells.…”

Section: G Screening Strategy For Er Gii Inhibitorsmentioning

confidence: 99%

Antiviral Activity and Mechanism of Action of Endoplasmic Reticulum Glucosidase Inhibitors: A Mini Review

Onda

Hakamata

2018

TIGG

Self Cite

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Antivirals are used to treat viral infections, and antibiotics are used to treat bacterial infections. However, the mechanisms of action and number of commercially available antivirals are very limited compared to those for antibiotics. Accordingly, our group is engaged in ongoing research to develop host-targeting antivirals for the virus infections. This work is primarily focused on the endoplasmic reticulum (ER) glucosidases involved in N-glycan synthesis as the host-dependent factors of viral infection. It is widely accepted that a key mechanism by which those inhibitors act as antivirals is their ability to disrupt virus glycoprotein folding via their inhibition of ER glucosidases. Importantly, very few virus strains are resistant to ER glucosidase inhibitors because ER glucosidase enzymes are not encoded on virus genomes. This avoids problems arising from resistance mutations occurring in the viral target. A number of ER glucosidase inhibitors with antiviral activity have been reported in the past, and several clinical trials of these have been performed. In this paper, we examine the factors preventing the development of these inhibitors as antivirals and our attempts to overcome them.

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Virtual ligand screening of α-glucosidase: Identification of a novel potent noncarbohydrate mimetic inhibitor

Cited by 7 publications

References 11 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

Virtual Screening Against Carbohydrate-Binding Proteins: Evaluation and Application to Bacterial Burkholderia ambifaria Lectin

Antiviral Activity and Mechanism of Action of Endoplasmic Reticulum Glucosidase Inhibitors: A Mini Review

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