Metalloenzymes are prevalent throughout the body and serve a wide array of functions in vivo.  These roles range from regulating blood pH and inflammation to controlling DNA expression and superoxide dismutation, to name but a few.  Given the importance of these functions, metalloenzyme misregulation can play a significant role in human disease. Typically, de novo designed metalloenzyme inhibitors incorporate a metal binding group (MBG) to ligate the catalytic metal and a backbone optimized for the desired metalloenzyme through structure-activity or structure-based drug design approaches.  Currently most inhibitors incorporate a hydroxamate, carboxylate, or thiolate MBG.  The use of only a few metal binding moieties raises concerns for off-target inhibition of metalloenzymes. A study on the cross-inhibitory activities of known metalloenzyme inhibitors against a panel of metalloproteins has been performed.  The inhibitors studied use atypical MBGs such as hydroxyurea and hydroxpyridinonate, as well as the more common hydroxamates and carboxylates.  The panel of metalloproteins included several matrix metalloproteinases, carbonic anhydrase, tyrosinase, histone deacetylase, angiotensin converting enzyme, and holo-transferrin.  This panel allowed for the comparison of zinc, copper, and iron metalloprotein cross-inhibition and metal removal.  Results indicate that this assortment of inhibitors and metalloenzymes remain extremely selective for their intended targets, even at high concentrations. These findings will help guide the design of novel metalloenzyme inhibitors that are specific as well as efficacious.

Metalloprotein cross-inhibition and metal ion removal by chelating inhibitors:  The impact of metal binding groups on selectivity

246th National Meeting (2013)

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