Transcript Elucidating Drug-Metalloprotein Interactions with Tris

U.C.S.D. News Media Workshop
Dec. 9, 2005
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
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What are Metalloproteins?
Hemoglobin requires Iron
A metalloprotein is simply a protein
that requires a metal to do its job.
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Proteases
x
 Proteases are proteins that ‘cut up’ other
proteins.
 Metalloprotein + Protease = Metalloprotease.
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Matrix Metalloprotease (MMP)
= Zinc
 MMP are important targets for heart disease.
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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
MMPi
Warhead
HDACi
LFi
Guidance System
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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 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
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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.)