1. 1 The chink in the armour: taking aim at metals in enzymes Seth M. Cohen Department of Chemistry and Biochemistry University of California, San Diego La Jolla, CA 92093-0358 U.C.S.D. News Media Workshop Dec. 9, 2005

2. 2 What are Metalloproteins? A metalloprotein is simply a protein that requires a metal to do its job. Hemoglobin - requires Iron

3. 3 Proteases Proteases are proteins that ‘cut up’ other proteins. Metalloprotein + Protease = Metalloprotease. x

4. 4 Matrix Metalloprotease (MMP) MMP are important targets for heart disease. = Zinc

5. 5 Histone Deacetylase (HDAC) HDAC are important targets for cancer.

6. 6 Anthrax Lethal Factor (LF) LF is an important target for anthrax. In all three cases the drug binds to the zinc.

7. 7 Drug Design - A Guided Missile Guidance System Warhead MMPi HDACi LFi

8. 8 Goal – Better Warheads A wide variety of guidance systems have been examined. The ‘warhead’ is the focus of our research efforts (hydroxamic acid alternatives) – a more powerful warhead should generate a more potent drug.

9. 9 New Warheads Using compounds already found in food and cosmetic products, we found improved warheads that are more effective at stopping metalloproteases.

10. 10 The Most Important Slide Current Members David T. Puerta Faith E. Jacobsen Jana A. Lewis Dr. Jay Stork Misha V. Golynskiy Sara R. Halper Sara Thoi Loi Do Former Members Ba L. Tran Talib C. Davis Scot A. Lieser Alexis Kaushansky Heather Delaney Carmen Velez David Tat Dr. Drew L. Murphy Prof. M.R. Malachowski Prof. G. Olivier-Lilley

11. 11 Acknowledgements Collaborators Prof. J. Andrew McCammon  John Mongan  Julie Schames  Dr. Richard Henchman Prof. Francisco Villarreal  Diego Romero-Perez  Michael Griffin  Dr. Ricardo Garcia Prof. Arnold Rheingold  Dr. Lev Zakharov Funding UCSD American Heart Association Research Corporation Hellman Family Fund NSF (CAREER award) ACS-PRF (AC and G grant) UCSD Moores Cancer Center UCSD Academic Senate ARCS, GAANN, and UC TSR&TP fellowships (J.A.L., F.E.J.) NSF fellowship (S.R.H.) NIH fellowship (D.T.P.)