Cisbio eBook - 15

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

Deposit Photos / tashatuvango

Now, they've developed a TR-FRET screening-based
assay to look for small molecule inhibitors of the
SOD1-Derlin-1 interaction. After screening 160,000
small molecules, they identified 44 that diminish
the FRET signal. They selected one promising candidate, for which dozens of structural analogs were
commercially available. Testing these analogs led
them to one that blocks SOD1-Derlin-1 interaction for all 122 SOD1 mutations that they tested.
The compound increased motor neuron survival in
human cell culture, and delayed the onset of symptoms in a SOD1 mutant mouse model.
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"I think they showed that this
is a very strong assay for HTS,"
says Adrian Israelson, PhD,
professor of cell and molecular
biology at Ben-Gurion University of the Negev, in Israel,
adding that it could open the
door to identifying other PPI
inhibitors in ALS and other
diseases. Israelson studies
how misfolded SOD1 leads to
motor neuron degeneration.
"Misfolded SOD1 associates
with spinal cord mitochondria and interacts with
VDAC1, the most important channel in the outer
mitochondrial membrane," he tells GEN. "This
interaction, for example, could be a potential
target for intervention."
Much remains to be learned before the new
finding translates to human treatment, points
out Hande Ozdinler, PhD, associate professor of
neurology at Northwestern University. Still, "this is
interesting from a drug discovery point of view,"
she says.

Ozdinler and her colleagues recently published
an extensive analysis of the protein-protein interactions relevant to ALS, in an effort to understand
how such a wide variety of seemingly unrelated
mutations all lead to the same disease pathology.
"The genes that are mutated in ALS patients
are not really linked," she says. "They must be
converging on some biological event." Reasoning
that "all biological events take place because
of protein-protein interactions," Ozdinler went
looking for common roles among the binding
partners of ALS-related genes.
From the myriad interactions, a few key
canonical pathways emerged, such as regulation of lipid and protein homeostasis, and DNA
damage repair. "We started realizing some of the
converging domains, and some proteins that
play really important key roles, so that you pull
them out of the interactome, the whole interactome domain collapses," Ozdinler says. These are
mutations that aren't even seen in patients, she
remarks, presumably because they are so critical
that they are embryonic lethal. But mutations
along these canonical pathways will pull the

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