title: Irreversible inhibition of human cathepsins B, L, S and K by hypervalent tellurium compounds.
abstract: The inhibition of human cysteine cathepsins B, L, S and K was evaluated by a set of hypervalent tellurium compounds (telluranes) comprising both organic and inorganic derivatives. All telluranes studied showed a time- and concentration-dependent irreversible inhibition of the cathepsins, and their second-order inactivation rate constants were determined. The organic derivatives were potent inhibitors of the cathepsins and clear specificities were detected, which were parallel to their known substrate specificities. In all cases, the activity of the tellurane-inhibited cathepsins was recovered by treatment of the inactivated enzymes with reducing agents. The maximum stoichiometry of the reaction between cysteine residues and telluranes were also determined. The presented data indicate that it is possible to design organic compounds with a tellurium(IV) moiety as a novel warhead that covalently modifies the catalytic cysteine, and which also form strong interactions with subsites of cathepsins B, L, S and K, resulting in more specific inhibition.
authors: Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Três de Maio 100, 04044-20 São Paulo, Brazil.
authors: Rodrigo L O R
authors: RL
authors: Cunha
authors: Iuri E
authors: IE
authors: Gouvêa
authors: Geovana P V
authors: GP
authors: Feitosa
authors: Márcio F M
authors: MF
authors: Alves
authors: Dieter
authors: D
authors: Brömme
authors: João V
authors: JV
authors: Comasseto
authors: Ivarne L S
authors: IL
authors: Tersariol
authors: Luiz
authors: L
authors: Juliano
mesh_terms: D002401:Cathepsin B / Q000037:antagonists & inhibitors; D056657:Cathepsin K / Q000037:antagonists & inhibitors; D056668:Cathepsin L / Q000037:antagonists & inhibitors; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D006801:Humans; D009930:Organic Chemicals / Q000737:chemistry* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013691:Tellurium / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D009930:Organic Chemicals; D011480:Protease Inhibitors; D002403:Cathepsins; D002401:Cathepsin B; D056668:Cathepsin L; C028217:cathepsin S; D056657:Cathepsin K; D013691:Tellurium