Abstract
Influenza 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.
Highlights
Influenza is a highly contagious acute viral infection with high morbidity and mortality rates in humans and animals worldwide [1]
We have previously reported that two compounds from this series—2-deoxy sugar derivatives of uridine (IW3 and IW7) (Figure 1)—showed good anti-influenza virus activity in vitro with IC50 of 72 and 63 μM, respectively [34]
Even though some of them showed good antiviral activity in vitro, most of their antiviral activity is still associated with the influenza viral replication process
Summary
Influenza is a highly contagious acute viral infection with high morbidity and mortality rates in humans and animals worldwide [1]. The H1N1 and H3N2 influenza virus subtypes are the most prevalent and the main reason for several recent pandemics in humans, including the 2009 H1N1 pandemic with high morbidity. Vaccines and prophylaxis with antiviral drugs are currently two main strategies used to control influenza infections. Vaccination strategies are the best method of prevention. They have to be updated regularly to account for antigenic changes of the viral glycoproteins. Due to the lack of effectiveness of vaccines against rapidly emerging mutant viruses during seasonal epidemics and sporadic pandemics, antiviral drugs against influenza virus may represent the first line of defence, especially in the beginning of an epidemic until a suitable, effective vaccine becomes available
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