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An NMR Study of the Inhibition of Proteases by Glyoxal Inhibitors

Paul Malthouse, Professor / Head of Subject for Biochemistry, University College Dublin

Date Posted: Thursday, May 22, 2008

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About the speaker

Paul Malthouse is currently Head of Biochemistry at University College Dublin. He obtained his Ph.D. in Biochemistry under the supervision of Professor Keith Brocklehurst studying the mechanism of the cysteine proteases. It was with Professor Ian Scott at Edinburgh and Texas A & M Universities that he first became interested in using NMR as a probe of protein structure and function. Most of his subsequent research at University College Dublin has utilised NMR and especially C13-NMR to study a range of proteins. Since 2000 his research has focussed on the interaction of the glyoxal inhibitors with the serine, cysteine, aspartyl and metalloproteases.


Proteases play an essential role in a range of diseases. The AIDS virus needs a
protease to multiply, cancers and parasites use proteases to move through tissues and proteases are used to produce the amyloid plaque protein which causes Alzheimer's disease. Proteases are also involved in the tissue destruction associated with arthritis and emphysema as well as the tissue remodelling associated with restenosis and atherosclerosis. Protease inhibitors are effective drugs for treating high blood pressure and AIDS but clearly they could play an important role in treating a range of medical conditions.

The rate limiting step in catalysis by proteases involves formation or breakdown of a tetrahedral intermediate. In the serine and cysteine proteases an enzyme
nucleophile reacts with the peptide carbonyl carbon to form a tetrahedral
intermediate while with the aspartyl and metalloproteases water reacts with the
peptide carbonyl to form the tetrahedral intermediate. Therefore transition state analogues that mimic these tetrahedral intermediates are expected to be potent
protease inhibitors.

The present work uses NMR to show that the glyoxal group (RCOCHO) is a versatile inhibitor warhead, which by adjusting its hydration state can mimic tetrahedral intermediates formed by different classes of protease [1,2,3,4].

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