Bicyclic peptidomimetics targeting secreted aspartic protease 2 (SAP2) from Candida albicans reveal a constrained inhibitory chemotype

Bioorg Med Chem. 2012 Dec 15;20(24):7206-13. doi: 10.1016/j.bmc.2012.09.031. Epub 2012 Oct 17.


The in vitro screening of stereoisomeric bicyclic peptidomimetics towards SAP2 of Candida albicans revealed a constrained chemotype as aspartic protease inhibitor in the micromolar to nanomolar range. The results indicated that the acetal bridge may serve as a transition-state isostere, and that the right match between interactions with subsites and the orientation by hydrogen bonding with Gly85 is the main requisite for inhibitory activity. Molecular docking calculations suggested the bicyclic acetal scaffold to be capable of interacting with the two catalytic aspartic acids, thus resulting in good inhibitory activity with only two hydrophobic groups addressing the enzyme catalytic subsites.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antifungal Agents / chemistry*
  • Antifungal Agents / pharmacology*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / chemistry
  • Candida albicans / drug effects
  • Candida albicans / enzymology*
  • Fungal Proteins / antagonists & inhibitors*
  • Fungal Proteins / chemistry
  • Molecular Docking Simulation
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology
  • Peptidomimetics / chemistry*
  • Peptidomimetics / pharmacology*
  • Stereoisomerism


  • Antifungal Agents
  • Fungal Proteins
  • Peptides, Cyclic
  • Peptidomimetics
  • Aspartic Acid Endopeptidases
  • SAP2 protein, Candida