Metalloprotein–Inhibitor Binding: Human Carbonic Anhydrase II as a Model for Probing Metal–Ligand Interactions in a Metalloprotein Active Site

Abstract

An ever increasing number of metalloproteins are being discovered that play essential roles in physiological processes. Inhibitors of these proteins have significant potential for the treatment of human disease, but clinical success of these compounds has been limited. Herein, Zn(II)-dependent metalloprotein inhibitors in clinical use are reviewed, and the potential for using novel metal-binding groups (MBGs) in the design of these inhibitors is discussed. By using human carbonic anhydrase II (hCAII) as a model system, the nuances of MBG-metal interactions in the context of a protein environment can be probed. Understanding how metal coordination influences inhibitor binding may help in the design new therapeutics targeting metalloproteins.

Discovery of an Inhibitor of the Proteasome Subunit Rpn11

“…54 Assays were carried out in 50 mM HEPES (pH 8.0). A BioTek Precision XS microplate sample processor was utilized.…”

Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11

“…hCAII was expressed and purified as previously reported 52 . Assays were run in 50 mM HEPES (pH 8.0).…”

Catalytic Metallodrugs: Substrate‐Selective Metal Catalysts as Therapeutics

“…[150] Sulfonamide derivatives are wellk nown for their inhibitory effect on CA activity through coordination of actives ite zinc. [150,151] Inactivation of CA-I by designed catalytic metallodrugs hasb een reported, [152] in which either Cu-phenanthroline [152a] or CuGGH [152b] have been incorporated into as ulfanilamide (SLN) derivative that interacts with the catalytic site of CA-I (Scheme 1). In the presence of ascorbate and dioxygen, Cu-phenanthroline-SLN derivatives were found to induce oxidative cleavageo fC A-I, while protein fragments from cleavage reactions were observed in SDS-PAGE experiments.…”