title: Terpyridine platinum(II) complexes inhibit cysteine proteases by binding to active-site cysteine.
abstract: Platinum(II) complexes have been demonstrated to form covalent bonds with sulfur-donating ligands (in glutathione, metallothionein and other sulfur-containing biomolecules) or coordination bonds with nitrogen-donating ligands (such as histidine and guanine). To investigate how these compounds interact with cysteine proteases, we chose terpyridine platinum(II) (TP-Pt(II)) complexes as a model system. By using X-ray crystallography, we demonstrated that TP-Pt(II) formed a covalent bond with the catalytic cysteine residue in pyroglutamyl peptidase I. Moreover, by using MALDI (matrix-assisted laser desorption/ionization) and TOF-TOF (time of flight) mass spectrometry, we elucidated that the TP-Pt(II) complex formed a covalent bond with the active-site cysteine residue in two other types of cysteine protease. Taken together, the results unequivocally showed that TP-Pt(II) complexes can selectively bind to the active site of most cysteine proteases. Our findings here can be useful in the design of new anti-cancer, anti-parasite or anti-virus platinum(II) compounds.
authors.affiliation: Department and Institute of Pharmacology, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Yan-Chung
authors.initials: YC
authors.lastname: Lo
authors.forename: Wen-Chi
authors.initials: WC
authors.lastname: Su
authors.forename: Tzu-Ping
authors.initials: TP
authors.lastname: Ko
authors.forename: Nai-Chen
authors.initials: NC
authors.lastname: Wang
authors.forename: Andrew H-J
authors.initials: AH
authors.lastname: Wang
mesh_terms: D000595:Amino Acid Sequence; D002384:Catalysis; D020134:Catalytic Domain / Q000187:drug effects; D003545:Cysteine / Q000737:chemistry*; D057056:Cysteine Proteases / Q000737:chemistry* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D015853:Cysteine Proteinase Inhibitors; D009944:Organoplatinum Compounds; D010455:Peptides; D057056:Cysteine Proteases; D003545:Cysteine