Molecular basis of R294K mutation effects of H7N9 neuraminidases with drugs and cyclic peptides: an in silico and experimental study

Abstract

In China, a recent outbreak of the new R294K H7N9 influenza has infected 134 people and killed 45 people since January 2014. Prof. Gao et al. reported that an R294K neuraminidase (Shanghai N9: R294K mutation; Anhui N9: no R294K mutation) results in multi-drug resistance with extreme oseltamivir resistance (over 100 000-fold). Herein, we report the findings of molecular simulations and computational alanine-scanning mutagenesis for cyclic peptide I with the neuraminidases of Shanghai N9 and Anhui N9 A. Our results suggest that cyclic peptide I can inhibit the Shanghai N9 and Anhui N9 influenza A virus neuraminidases. The peptide can provide efficient binding affinities to Shanghai N9 either by the five residues (Arg119, Ile277, Lys294, Arg372 and Tyr406) mutations or by the 13 residues (Val117, Gln137, Thr149, Hie151, Asp152, Ser154, Ile224, Asn296, Asn347, Asn348, Ile429, Pro433 and Lys434) analyzed by binding mode analysis. However, the four residues (Ile150, Arg153, Gln155 and Arg157) can obviously affect the binding interactions among the cyclic peptide.