Cisbio eBook - 16

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

equilibrium in one direction or another, she says,
gradually accumulating stresses until the system
falls apart.
"If cellular events are modulated by these interactions, and if you can block them or enhance the
interaction, you may also expedite or block that
cellular event," Ozdinler says. Understanding the
complex interactome network, therefore, could
light the way to new drug targets that could
restore properly functioning interactions.

Rebuffing Infectious Diseases
Antibiotics revolutionized medicine when they
became widely available in the 1940s, but during
the intervening decades, pathogenic bacteria
have evolved resistance time and again. Yet
even considering the great need, the development of new antibiotics has slowed to a crawl in
recent years. To fill this void, some researchers are
looking to PPI inhibitors.
"There's only so many essential enzymes in
bacteria," says Andrew Voter. "We've sort of

16 | GENengnews.com

run out of other things to target." And unlike
enzymes, PPIs potentially offer greater specificity.
"If you're targeting enzymatic activity, likely your
human cell and your bacterial cell are going to
be acting on the same substrate," he points out.
With PPIs, there's more opportunity to target
something that's going to be pathogen-specific,
causing fewer side effects.
One way that PPIs offer an end run around drug
resistance is by providing targets that inhibit virulence without killing the bacteria. For instance,
bacteria that cause urinary tract infections rely on
various types of hairlike pili to anchor themselves
against the flow of urine that could otherwise flush
them out of the body. Pilicides can target the interaction between the pili and the bladder epithelial
cells, preventing infection without harming any
non-pathogenic bacteria in their path.
Antivirals targeting PPIs are also on the rise.
Viruses pack light, and need to hijack scads of
host proteins to do their work. Two key steps
in the viral life cycle involve PPIs: getting into

the cell, and integrating the viral genome into
the host genome. The anti-HIV drug maraviroc, approved in 2007, targets the interaction
between the viral gp120 and the cell surface
receptor CCR5, preventing the virus from
entering the cell.
More recently, inhibitors have been discovered
that block the interaction between HIV integrase with the host factor LEDGF/p75. Zeger
Debyser, MD, PhD, at KU Leuven in Flanders,
Belgium, and colleagues have reported on these
inhibitors, which they call LEDGINs. LEDGF/p75
tethers the virus to the chromatin where it can
be incorporated into an area of active transcription. LEDGINs inhibit allosterically, reducing the
catalytic activity of the integrase and preventing
integration.
All pathogens, of course, depend on host-protein
interactions to get in and do their dirty work. As
more sophisticated tools become available, more
of these interactions will prove invaluable for
halting the spread of infection. n


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