title: Serum albumin as a probe for testing the selectivity of irreversible cysteine protease inhibitors: The case of vinyl sulfones.
abstract: Vinyl sulfones are used for drug design of irreversible inhibitors of cysteine proteases since they are able to alkylate cysteine thiols inside the catalytic pocket of this class of enzymes. Some authors have reported the lack of reactivity towards glutathione as sufficient evidence of the selectivity of such a mechanism. Herein, we demonstrate that some simple molecules containing a vinyl sulfone moiety are not thiol-specific alkylants since they react with some albumin nucleophiles including side chains of Cys34 and His146. Such side-reactions are not desirable for any drug candidate since they limit serum stability, bioavailability and they possibly trigger toxicity mechanisms. In silico predictions, indicate that the compounds tested share similar structural features with reported inhibitors of cysteine proteases, as well as similar poses around the main albumin nucleophiles. Altogether, the data suggest that albumin is better than glutathione for the setup of early in vitro tests probing the selectivity of cysteine protease inhibitors.
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano, via Mangiagalli 25, 20133 Milan, Italy. Electronic address: luca.regazzoni@unimi.it.
authors.forename: Luca
authors.initials: L
authors.lastname: Regazzoni
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano, via Mangiagalli 25, 20133 Milan, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Colombo
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano, via Mangiagalli 25, 20133 Milan, Italy.
authors.forename: Angelica
authors.initials: A
authors.lastname: Mazzolari
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano, via Mangiagalli 25, 20133 Milan, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Vistoli
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano, via Mangiagalli 25, 20133 Milan, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Carini
mesh_terms: D000595:Amino Acid Sequence; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D015335:Molecular Probes / Q000737:chemistry*; D012709:Serum Albumin / Q000737:chemistry*; D013450:Sulfones / Q000737:chemistry*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D015335:Molecular Probes; D012709:Serum Albumin; D013450:Sulfones; C009873:divinyl sulfone
keywords: Albumin; Covalent modification; Cys34; Cysteine protease inhibitors; His146; Vinyl sulfones