Cyclic peptide-based potent human SIRT6 inhibitors

Org Biomol Chem. 2016 Jul 7;14(25):5928-35. doi: 10.1039/c5ob02339d. Epub 2016 Jun 1.

Abstract

We discovered in the current study that six side chain-to-side chain cyclic pentapeptides harboring a central N(ε)-dodecyl (or tetradecyl)-thiocarbamoyl-lysine residue all behaved as highly potent (nM level) inhibitors against human SIRT6-catalyzed deacylation reaction. Moreover, one compound was also found to be selective for SIRT6 versus SIRT2/3/5 (∼20-, ∼11-, and >940-fold, respectively), despite its modest (∼2.3-fold) SIRT6 inhibitory selectivity versus SIRT1. These compounds could be valuable leads for the identification of further potent and selective human SIRT6 inhibitors.

MeSH terms

  • Histone Deacetylase Inhibitors / chemistry*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Peptides, Cyclic / chemistry*
  • Peptides, Cyclic / pharmacology*
  • Protein Domains
  • Sirtuins / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Histone Deacetylase Inhibitors
  • Peptides, Cyclic
  • SIRT6 protein, human
  • Sirtuins