The de-guanidinylated derivative of peramivir remains a potent inhibitor of influenza neuraminidase

Bioorg Med Chem Lett. 2011 Dec 1;21(23):7137-41. doi: 10.1016/j.bmcl.2011.09.076. Epub 2011 Sep 24.

Abstract

The guanidine function in the potent neuraminidase inhibitor peramivir was included early on in the drug design process, and examination of X-ray structural data for the enzyme-inhibitor complex would seem to indicate that the guanidine plays a critical role in promoting binding. However, this functional group may also contribute to the poor oral availability of the drug. Given that the relative stereochemistry on the guanidine-bearing carbon in peramivir is opposite to that in zanamivir (a related neuraminidase inhibitor, for which the guanidine function is known to contribute substantially to the potency), we sought to determine the importance of the guanidine group to peramivir's overall potency. Here we report that the de-guanidinylated analogue of peramivir is only ca. 1-order of magnitude less potent than peramivir itself in two in vitro inhibition assays. This suggests that next-generation inhibitors designed to improve on peramivir's properties might profitably dispense with the guanidine function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acids, Carbocyclic
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Crystallography, X-Ray
  • Cyclopentanes / chemical synthesis*
  • Cyclopentanes / chemistry
  • Cyclopentanes / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Guanidines / chemical synthesis*
  • Guanidines / chemistry
  • Guanidines / pharmacology*
  • Humans
  • Influenza A virus* / drug effects
  • Influenza A virus* / enzymology
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Structure
  • Neuraminidase / antagonists & inhibitors*
  • Neuraminidase / genetics
  • Protein Binding
  • Recombinant Proteins / genetics
  • Zanamivir / chemistry
  • Zanamivir / pharmacology

Substances

  • Acids, Carbocyclic
  • Antiviral Agents
  • Cyclopentanes
  • Enzyme Inhibitors
  • Guanidines
  • Recombinant Proteins
  • Neuraminidase
  • Zanamivir
  • peramivir