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.

Key words: Platinum(II); Enzyme activity; Cysteine protease inhibitors; Crystal structure.

This article can be cited as:
Yan-Chung Lo, Wen-Chi Su, Tzu-Ping Ko, Nai-Chen Wang, Andrew H.-J. Wang. Terpyridine Platinum(II) Complexes Inhibit Cysteine Proteases by Binding to Active-site Cysteine. J. Biomol Struct Dyn 29(2) 267- 282(2011).