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The chink in the armour: taking aim

at metals in enzymes

Seth M. Cohen

Department of Chemistry and BiochemistryUniversity of California, San Diego

La Jolla, CA 92093-0358

U.C.S.D. News Media WorkshopDec. 9, 2005

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What are Metalloproteins?

A metalloprotein is simply a protein that requires a metal to do its job.

Hemoglobin - requires Iron

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Proteases

Proteases are proteins that ‘cut up’ other proteins.

Metalloprotein + Protease = Metalloprotease.

x

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Matrix Metalloprotease (MMP)

MMP are important targets for heart disease.

= Zinc

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Histone Deacetylase (HDAC)

HDAC are important targets for cancer.

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Anthrax Lethal Factor (LF)

LF is an important target for anthrax.In all three cases the drug binds to the zinc.

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Drug Design - A Guided Missile

Guidance System

WarheadMMPi

HDACi

LFi

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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.

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New Warheads

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

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The Most Important SlideCurrent MembersDavid T. PuertaFaith E. JacobsenJana A. LewisDr. Jay StorkMisha V. GolynskiySara R. HalperSara ThoiLoi Do

Former MembersBa L. TranTalib C. DavisScot A. LieserAlexis KaushanskyHeather DelaneyCarmen VelezDavid TatDr. Drew L. MurphyProf. M.R. MalachowskiProf. G. Olivier-Lilley

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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.)