Susceptibility of antiviral drugs against 2009 influenza A (H1N1) virus.

The recent outbreak of the novel strain of influenza A (H1N1) virus has raised a global concern of the future risk of a pandemic. To understand at the molecular level how this new H1N1 virus can be inhibited by the current anti-influenza drugs and which of these drugs it is likely to already be resistant to, homology modeling and MD simulations have been applied on the H1N1 neuraminidase complexed with oseltamivir, and the M2-channel with adamantanes bound. The H1N1 virus was predicted to be susceptible to oseltamivir, with all important interactions with the binding residues being well conserved. In contrast, adamantanes are not predicted to be able to inhibit the M2 function and have completely lost their binding with the M2 residues. This is mainly due to the fact that the M2 transmembrane of the new H1N1 strain contains the S31N mutation which is known to confer resistance to adamantanes.

[1]  E. De Clercq,et al.  Antiviral agents active against influenza A viruses , 2006, Nature reviews. Drug discovery.

[2]  David J. Stevens,et al.  The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design , 2006, Nature.

[3]  Erik De Clercq,et al.  Antiviral agents active against influenza A viruses , 2006, Nature Reviews Drug Discovery.

[4]  Guy Boivin,et al.  Susceptibility of recent Canadian influenza A and B virus isolates to different neuraminidase inhibitors. , 2002, Antiviral research.

[5]  R. Bertram,et al.  Backbone structure of the amantadine-blocked trans-membrane domain M2 proton channel from Influenza A virus. , 2007, Biophysical journal.

[6]  David S. Goodsell,et al.  Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function , 1998, J. Comput. Chem..

[7]  Mark A. Miller,et al.  The genesis and spread of reassortment human influenza A/H3N2 viruses conferring adamantane resistance. , 2007, Molecular biology and evolution.

[8]  Thanyada Rungrotmongkol,et al.  How amantadine and rimantadine inhibit proton transport in the M2 protein channel. , 2008, Journal of molecular graphics & modelling.

[9]  黄亚明.  MedScape , 2009 .

[10]  Vasiliy P. Mishin,et al.  Susceptibilities of Antiviral-Resistant Influenza Viruses to Novel Neuraminidase Inhibitors , 2005, Antimicrobial Agents and Chemotherapy.

[11]  Alan J. Hay,et al.  Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants , 2008, Nature.

[12]  Thanyada Rungrotmongkol,et al.  Understanding of known drug‐target interactions in the catalytic pocket of neuraminidase subtype N1 , 2008, Proteins.

[13]  Thanyada Rungrotmongkol,et al.  Why Amantadine Loses Its Function in Influenza M2 Mutants: MD Simulations , 2009, J. Chem. Inf. Model..

[14]  M G Ford,et al.  Binding constants of neuraminidase inhibitors: An investigation of the linear interaction energy method. , 1999, Journal of medicinal chemistry.

[15]  Supot Hannongbua,et al.  On the lower susceptibility of oseltamivir to influenza neuraminidase subtype N1 than those in N2 and N9. , 2007, Biophysical journal.

[16]  N. Cox,et al.  Adamantane resistance among influenza A viruses isolated early during the 2005-2006 influenza season in the United States. , 2006, JAMA.

[17]  J. Tang,et al.  Emergence of adamantane‐resistant influenza A(H3N2) viruses in Hong Kong between 1997 and 2006 , 2008, Journal of medical virology.

[18]  Thanyada Rungrotmongkol,et al.  How does each substituent functional group of oseltamivir lose its activity against virulent H5N1 influenza mutants? , 2009, Biophysical chemistry.

[19]  Thanyada Rungrotmongkol,et al.  Source of oseltamivir resistance in avian influenza H5N1 virus with the H274Y mutation , 2009, Amino Acids.

[20]  G. Boivin,et al.  Activity of the neuraminidase inhibitor A-315675 against oseltamivir-resistant influenza neuraminidases of N1 and N2 subtypes. , 2008, Antiviral research.

[21]  J. Chou,et al.  Mechanism of drug inhibition and drug resistance of influenza A M2 channel , 2009, Proceedings of the National Academy of Sciences.