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In Vitro Disassembly of Influenza A Virus Capsids by Gradient Centrifugation
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Mechanism of 150-cavity formation in influenza neuraminidase

Rommie E Amaro1, Robert V Swift, Lane Votapka

  • 1Department of Pharmaceutical Sciences, Computer Science and Chemistry, University of California, Irvine, California 92697, USA. ramaro@uci.edu

Nature Communications
|July 14, 2011
PubMed

Insights

Influenza neuraminidase (NA) drug targets are key to combating antiviral resistance. Biophysical simulations reveal the 2009 H1N1 NA preferentially exists with an open 150-cavity, crucial for drug development.

Area of Science:

  • Virology
  • Structural Biology
  • Drug Discovery

Background:

  • Influenza A neuraminidase (NA) is a target for antiviral drugs.
  • Antiviral resistance is an increasing problem in influenza treatment.
  • The 150-cavity in group-1 NA proteins is a potential drug target.

Purpose of the Study:

  • To investigate the solution structure of 2009 H1N1 pandemic virus neuraminidase (09N1 NA).
  • To understand the structural basis for the presence or absence of the 150-cavity in 09N1 NA.
  • To identify factors stabilizing the 150-cavity for drug design.

Main Methods:

  • Biophysical simulations (1.6 μs total).
  • Comparative simulations with avian N1, human N2, and a mutated 09N1.
  • Bioinformatics analysis.

Main Results:

  • 09N1 NA exists preferentially with an open 150-cavity in solution.
  • A conserved salt bridge is crucial for stabilizing the 150-cavity.
  • This stabilization is observed across different NA subtypes.

Conclusions:

  • The 150-cavity is present in solution for 09N1 NA, contrary to crystal structures.
  • Structural understanding of the 150-cavity aids in developing antivirals against resistant strains.
  • Antiviral compounds targeting the 150-cavity can inactivate both pandemic H1N1 and avian H5N1 viruses.

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