March
22, 2004
UCSD Pharmacologists Collaborate On New Approach To
Drug Design
By Sue Pondrom
French and American
researchers have developed a unique approach to drug design
where an important neuron-signaling enzyme called acetylcholinesterase
(AChE) acts as a microscopic vessel filled with reactant chemicals,
to create its own, tailored therapeutic agent.
While current AChE
inhibitors are widely used to treat neuromuscular and cognitive
disorders, the new process offers the potential for development
of more potent drugs with fewer side effects.
Published in a recent
issue of Proceedings of the National Academy of Sciences
(PNAS) (February 10, 2004), the study described how the
AChE molecule, serving as a surface, or template for the reactions,
brings the reactant components into proximity to form an inhibitor
of the enzyme that is both potent and highly specific for the
enzyme.
The investigators from
the French National Center for Scientific Research, the University
of California, San Diego (UCSD) and The Scripps Research Institute
(TSRI), noted that the formation of the inhibitor on the enzyme
template proceeds about a million times more rapidly than under
typical laboratory conditions in test tubes.
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Palmer
Taylor, Ph.D. |
“The enzyme template
is a fluctuating structure with many inherent conformations,”
said one of the study’s authors, Palmer Taylor, Ph.D.,
dean of the UCSD School of Pharmacy and Pharmaceutical Sciences.
“The imaginative synthetic ‘click chemistry’
developed by the TSRI group headed by K. Barry Sharpless, freezes
‘in-frame,’ like a single frame of a motion picture,
the conformation selective for the inhibitor.”
He added that “while
the compounds formed by click chemistry have high affinity for
their targets, the real potential lies in the selectivity of
the inhibitor formed on the target surface for one of the many
closely related enzymes or drug receptors.”
The study was led by
structural biochemists, Drs. Pascale Marchot and Yves Bourne,
currently with the French National Center for Scientific Research
in Marseille, France, and formerly visiting faculty at the UCSD
School of Medicine and TSRI. A key role in the research was
played by Taylor, also a UCSD professor of pharmacology, and
project scientist Zoran Radic, Ph.D. The UCSD team characterized
the binding sites, the conformation and the structural fluctuations
in AChE, and the molecular template on which the chemical reactions
occurred.
Click chemistry, that
facilities specific chemical reactions on an enzyme or drug
target surface, is a process developed three years ago by Sharpless,
who, with colleague Hartmuth Kolb, Ph.D., participated in the
research by characterizing the detailed reaction mechanism and
product formed from a combination of reactants.
The work was supported
by grants from the Association Francaise contre les Myopathies,
the U.S. Public Health Service, the Department of Army Medical
Defense, the National Institutes of Health, the National Science
Foundation, and the W.M. Keck Foundation.
Contact: Sue
Pondrom (619) 543-6163
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