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Tunable Probes with Direct Fluorescence Signals for the Constitutive and Immunoproteasome
Author(s) -
Dubiella Christian,
Cui Haissi,
Groll Michael
Publication year - 2016
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201605753
Subject(s) - electrophile , chemistry , proteases , proteasome , fluorescence , leaving group , combinatorial chemistry , sulfonate , reactivity (psychology) , macromolecule , biophysics , enzyme , sulfonyl , biochemistry , stereochemistry , organic chemistry , biology , catalysis , medicine , sodium , physics , alternative medicine , alkyl , pathology , quantum mechanics
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 p K a 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.