Cyclobutane-containing peptides: Evaluation as novel metallocarboxypeptidase inhibitors and modelling of their mode of action

Daniel Fernández, Elisabeth Torres, Francesc X. Avilés, Rosa M. Ortuño, Josep Vendrell

Research output: Contribution to journalArticleResearchpeer-review

42 Citations (Scopus)

Abstract

Different types of cyclobutane-containing peptides (CBPs) were screened for the first time as ligands of metallocarboxypeptidases (MCPs). CBPs are conformationally constrained, low molecular-weight compounds which showed moderate yet selective inhibitory activity against mammalian MCPs. The most potent compound was a carboxypeptidase B inhibitor. Docked protein-ligand complexes indicated that CBPs may bind to the target proteases via electrostatic interactions and aromatic stacking to catalytically crucial residues and that the placement of functional groups seems to be assisted by the rigid CBP backbone. The easily obtainable CBPs may offer a valuable alternative in the design of novel inhibitors to disease-linked metallocarboxypeptidases like human plasma carboxypeptidase B. © 2009 Elsevier Ltd. All rights reserved.
Original languageEnglish
Pages (from-to)3824-3828
JournalBioorganic and Medicinal Chemistry
Volume17
DOIs
Publication statusPublished - 1 Jun 2009

Keywords

  • Cyclobutane β-peptide
  • Human carboxypeptidase B
  • Inhibitor screening
  • Ligand docking
  • Metalloprotease
  • Non-natural amino acid

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