Tunable Probes with Direct Fluorescence Signals for the Constitutive and Immunoproteasome

Angew Chem Int Ed Engl. 2016 Oct 10;55(42):13330-13334. doi: 10.1002/anie.201605753.

Abstract

Electrophiles are commonly used for the inhibition of proteases. Notably, inhibitors of the proteasome, a central determinant of cellular survival and a target of several FDA-approved drugs, are mainly characterized by the reactivity of their electrophilic head groups. We aimed to tune the inhibitory strength of peptidic sulfonate esters by varying the leaving groups. Indeed, proteasome inhibition correlated well with the pKa of the leaving group. The use of fluorophores as leaving groups enabled us to design probes that release a stoichiometric fluorescence signal upon reaction, thereby directly linking proteasome inactivation to the readout. This principle could be applicable to other sulfonyl fluoride based inhibitors and allows the design of sensitive probes for enzymatic studies.

Keywords: fluorescent probes; inhibitors; probe design; proteasome; structure-activity relationships.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Fluorescence*
  • Fluorescent Dyes / chemistry
  • Fluorescent Dyes / pharmacology*
  • Humans
  • Molecular Structure
  • Proteasome Endopeptidase Complex / chemistry
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors / chemistry
  • Proteasome Inhibitors / pharmacology*
  • Sulfinic Acids / chemistry
  • Sulfinic Acids / pharmacology*

Substances

  • Fluorescent Dyes
  • Proteasome Inhibitors
  • Sulfinic Acids
  • sulfuryl fluoride
  • Proteasome Endopeptidase Complex