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Peramivir analogues bearing hydrophilic side chains exhibit higher activities against H275Y mutant than wild-type influenza virus

Abstract

Peramivir is an effective anti-influenza drug in clinical treatment of influenza, but its efficacy toward the H275Y mutant is reduced. The previously reported cocrystal structures of inhibitors in the mutant neuraminidase (NA) suggest that the hydrophobic side chain should be at the origin of reduced binding affinity. In contrast, zanamivir having a hydrophilic glycerol side chain still possesses high affinity to the H275Y NA. We thus designed five peramivir analogues (5−9) carrying hydrophilic glycol or glycerol side chains, and evaluated their roles in anti-influenza activity, especially for the H275Y mutant. The synthetic sequence involves a key step of (3+2) cycloaddition reactions between alkenes and nitrile oxides to construct the scaffold of peramivir carrying the desired hydrophilic side chains and other appropriate functional groups. The molecular docking experiments reveal that the hydrophilic side chain can provide extra hydrogen bonding with the translocated Glu-276 residue in the H275Y NA active site. Thus, the H275Y mutant may be even more sensitive than wild-type virus toward the peramivir analogues bearing hydrophilic side chains. Notably, the peramivir analogue bearing a glycerol side chain inhibits H275Y mutant with IC50 = 35 nM, better than WSN virus by 9 fold.

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Publication details

The article was received on 22 Sep 2017, accepted on 09 Nov 2017 and first published on 09 Nov 2017


Article type: Paper
DOI: 10.1039/C7OB02374J
Citation: Org. Biomol. Chem., 2017, Accepted Manuscript
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    Peramivir analogues bearing hydrophilic side chains exhibit higher activities against H275Y mutant than wild-type influenza virus

    D. Chiu, T. Lin, W. Huang, T. R. Cheng, K. Tsai and J. Fang, Org. Biomol. Chem., 2017, Accepted Manuscript , DOI: 10.1039/C7OB02374J

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