Biological evaluation of uridine derivatives of 2-deoxy sugars as potential antiviral compounds against influenza A virus
Ewelina Król , Ilona Wandzik , Martyna Krejmer-Rąbalska , Bogusław Szewczyk
AbstractInfluenza virus infection is a major cause of morbidity and mortality worldwide. Due to the limited ability of currently available treatments, there is an urgent need for new anti-influenza drugs with broad spectrum protection. We have previously shown that two 2-deoxy sugar derivatives of uridine (designated IW3 and IW7) targeting the glycan processing steps during maturation of viral glycoproteins show good anti-influenza virus activity and may be a promising alternative approach for the development of new anti-influenza therapy. In this study, a number of IW3 and IW7 analogues with different structural modifications in 2-deoxy sugar or uridine parts were synthesized and evaluated for their ability to inhibit influenza A virus infection in vitro. Using the cytopathic effect (CPE) inhibition assay and viral plaque reduction assay in vitro, we showed that compounds 2, 3, and 4 exerted the most inhibitory effect on influenza virus A/ostrich/Denmark/725/96 (H5N2) infection in Madin-Darby canine kidney (MDCK) cells, with 50% inhibitory concentrations (IC50) for virus growth ranging from 82 to 100 (μM) without significant toxicity for the cells. The most active compound (2) showed activity of 82 μM with a selectivity index value of 5.27 against type A (H5N2) virus. Additionally, compound 2 reduced the formation of HA glycoprotein in a dose-dependent manner. Moreover, an analysis of physicochemical properties of studied compounds demonstrated a significant linear correlation between lipophilicity and antiviral activity. Therefore, inhibition of influenza A virus infection by conjugates of uridine and 2-deoxy sugars is a new promising approach for the development of new derivatives with anti-influenza activities.
|Journal series||International Journal of Molecular Sciences, ISSN 1661-6596, e-ISSN 1422-0067|
|Publication size in sheets||0.65|
|Keywords in English||influenza A virus, antiviral compounds, uridine, 2-deoxy sugars, glycosylation inhibition|
|License||Journal (articles only); published final; ; with publication|
|Score|| = 30.0, 26-01-2018, ArticleFromJournal|
= 30.0, 26-01-2018, ArticleFromJournal
|Publication indicators||: 2016 = 3.226 (2) - 2016=3.482 (5)|
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