Cisbio eBook - 11

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

Two features that make macrocyclic peptides
desirable therapeutic options are the easiness of
manufacture and their lower toxicity and immunogenicity as compared to other molecules. "The
downside of macrocyclic peptides is that the cell
membrane is impermeable to almost all of them,
and that makes their target inaccessible," explains
Pei. Therefore, introducing macrocycles into cells
is a critical aspect of their therapeutic development. "We discovered a family of cyclic peptides
that are very efficient in going into the cell and
they can also take other cargo molecules with
them," continues Pei.
Recently, Pei and colleagues synthesized cell-

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permeable bicyclic peptides in which the two
rings contained different peptide sequences for
target binding and cell-penetrating motifs. "We
designed a combinatorial library in a way that
guarantees cell entry and target engagement,"
says Pei. This strategy led to the identification
of a potent and cell-permeable compound that
inhibited NF-κB signaling and the proliferation
of cisplatin-resistant ovarian cancer cells in vitro,
emerging as a promising strategy to develop
anti-inflammatory and anticancer drugs.
"One thing that could make a difference in the
future are small molecules that can allosterically
inhibit protein-protein interaction," notes Pei.

Allosteric inhibitors bind sites that are distinct
from the active site and lead to conformational
changes that modulate protein function. "This
will not be a general solution but certainly will
provide some applications for certain protein-
protein interaction targets," says Pei.
Another attractive set of therapeutic targets
comprises molecules that can bind cryptic
binding sites. These are binding sites that cannot
be seen in the most stable conformation of a
protein, but in alternative conformation in which
the protein may exist for a fraction of the time.
"That alternative conformation might have a
binding pocket that one can inhibit," notes Pei. n

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