Immunoproteasome β5i-Selective Dipeptidomimetic Inhibitors

ChemMedChem. 2016 Oct 6;11(19):2127-2131. doi: 10.1002/cmdc.201600384. Epub 2016 Aug 25.

Abstract

N,C-capped dipeptides belong to a class of noncovalent proteasome inhibitors. Herein we report that the insertion of a β-amino acid into N,C-capped dipeptides markedly decreases their inhibitory potency against human constitutive proteasome β5c, while maintaining potent inhibitory activity against human immunoproteasome β5i, thereby achieving thousands-fold selectivity for β5i over β5c. Structure-activity relationship studies revealed that β5c does not tolerate the β-amino acid based dipeptidomimetics as does β5i. In vitro, one such compound was found to inhibit human T cell proliferation. Compounds of this class may have potential as therapeutics for autoimmune and inflammatory diseases with less mechanism-based cytotoxicity than agents that also inhibit the constitutive proteasome.

Keywords: T cells; autoimmune; immunosuppression; peptidomimetics; β-amino acids; β5i-selective inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry
  • Amino Acids / pharmacology*
  • CD4-Positive T-Lymphocytes / drug effects
  • Cell Proliferation / drug effects
  • Dipeptides / chemical synthesis
  • Dipeptides / chemistry
  • Dipeptides / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Peptidomimetics / chemical synthesis
  • Peptidomimetics / chemistry
  • Peptidomimetics / pharmacology*
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors / chemical synthesis
  • Proteasome Inhibitors / chemistry
  • Proteasome Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Amino Acids
  • Dipeptides
  • Peptidomimetics
  • Proteasome Inhibitors
  • Proteasome Endopeptidase Complex