Development and characterization of lysine based tripeptide analogues as inhibitors of Sir2 activity

Bioorg Med Chem. 2009 Dec 1;17(23):8060-72. doi: 10.1016/j.bmc.2009.10.003. Epub 2009 Oct 9.


Sirtuins are NAD(+) dependent deacetylases that modulate various essential cellular functions. Development of peptide based inhibitors of Sir2s would prove useful both as pharmaceutical agents and as effectors by which downstream cellular alterations can be monitored. Click chemistry that utilizes Huisgen's 1,3-dipolar cycloaddition permits attachment of novel modifications onto the side chain of lysine. Herein, we report the synthesis of peptide analogues prepared using click reactions on Nepsilon-propargyloxycarbonyl protected lysine residues and their characterization as inhibitors of Plasmodiumfalciparum Sir2 activity. The peptide based inhibitors exhibited parabolic competitive inhibition with respect to acetylated-peptide substrate and parabolic non-competitive inhibition with NAD(+) supporting the formation of EI(2) and E.NAD(+).I(2) complexes. Cross-competition inhibition analysis with the non-competitive inhibitor nicotinamide (NAM) ruled out the possibility of the NAM-binding site being the second inhibitor binding site, suggesting the presence of a unique alternate pocket accommodating the inhibitor. One of these compounds was also found to be a potent inhibitor of the intraerythrocytic growth of P.falciparum with 50% inhibitory concentration in the micromolar range.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / chemical synthesis*
  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Binding Sites
  • Binding, Competitive / drug effects
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Kinetics
  • Lysine / analogs & derivatives*
  • Lysine / chemical synthesis
  • Lysine / chemistry
  • Lysine / pharmacology
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology
  • Plasmodium falciparum / growth & development
  • Sirtuin 2 / antagonists & inhibitors
  • Sirtuin 2 / metabolism*
  • Spectroscopy, Fourier Transform Infrared


  • Antimalarials
  • Enzyme Inhibitors
  • Oligopeptides
  • Sirtuin 2
  • Lysine