Cisbio eBook - 13

Trends in Protein-Protein Interactions Research | Targeting Protein-Protein Interactions Yields a Cornucopia of New Therapies

Arkin points out that PPIs run the gamut from
simple, short peptide epitopes, to secondary
structures, like alpha-helixes, that bind to a
simple complementary groove, to intricate
folding arrangements in both partners that
are much harder to inhibit. Even in the smooth
expanse of the "catcher's mitt," Arkin has shown
that often, most of the binding energy localizes
to "hot spots," clusters of key residues about the
same size as a small molecule. These hot spots,
she says, could dynamically adjust to bind to a
small molecule, making screening for inhibitors
fairly straightforward.

Undruggable...or Unscreenable?
Another obstacle to discovering new PPI inhibitors
is the lack of libraries designed to hunt for them,
points out Philippe Roche, PhD, senior scientist at
the Integrative Structural and Chemical Biology
team at the Cancer Research Center of Marseilles,
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face had been 3D characterized. From analyzing
these known PPI inhibitors, and what structures
they had in common, Roche and his colleagues
developed a model to predict whether
compounds would likely inhibit PPIs. Using this
method, 2P2Idb creates an enriched screening
library that dramatically increases the hit rate
compared to standard libraries.

Getty Images / Aunt_Spray

of the Small Molecule Discovery Center at The
University of California, San Francisco (UCSF).
"There are hundreds of thousands of them, and
they're very diverse."

Having proven their success with a small library
of 1600 compounds, they are in the process of
expanding the library to 10,000 compounds.
Once that's published, "the idea is to make this
library available to labs around the world," Roche
says. "We will provide the library free of charge for
people to be able to screen PPI targets."
France. "If you screen PPIs using libraries that were
designed for kinases or GPCR, that's why you don't
get a lot of good results," he says.
To that end, his group began assembling a library
focused on orthosteric inhibitors of PPIs. The
result was 2P2Idb, a hand-curated, structural
database cataloging orthosteric inhibitors of
protein-protein interactions for which the inter-

Cancer in the Crosshairs
Last year, scientists at Emory University unveiled
the OncoPPi network, a large-scale map of
protein-protein interactions relevant to cancer.
By understanding the complex cross-talk of
various oncogenic pathways, the researchers
hoped to reveal strategies for taking down key
proteins previously impervious to drug targeting.

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