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.
Serum albumin as a probe for testing the selectivity of irreversible cysteine protease inhibitors : the case of vinyl sulfones / L. Regazzoni, S. Colombo, A. Mazzolari, G. Vistoli, M. Carini. - In: JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS. - ISSN 0731-7085. - 124(2016 May 30), pp. 294-302. [10.1016/j.jpba.2016.02.056]
Serum albumin as a probe for testing the selectivity of irreversible cysteine protease inhibitors : the case of vinyl sulfones
L. Regazzoni
;S. ColomboSecondo
;A. Mazzolari;G. VistoliPenultimo
;M. CariniUltimo
2016
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.File | Dimensione | Formato | |
---|---|---|---|
1-s2.0-S0731708516301182-main.pdf
accesso riservato
Tipologia:
Publisher's version/PDF
Dimensione
1.41 MB
Formato
Adobe PDF
|
1.41 MB | Adobe PDF | Visualizza/Apri Richiedi una copia |
Pubblicazioni consigliate
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.