Cisbio eBook - 10

Trends in Protein-Protein Interactions Research | Protein-Protein Interactions: Lessons from the Past and Current Directions

When targeting protein-protein interactions, the
main challenge is that typical interfaces do not
have well-defined binding pockets, according
to Dehua Pei, PhD, professor of chemistry and
biochemistry at The Ohio State University. While
small molecules are ideal for targeting deep
binding pockets in proteins, they do not bind with
sufficiently high affinity to flat interfaces, which are
usually involved in protein-protein interactions.
"This makes protein-protein interfaces undruggable by conventional methods," says Pei. This
challenge can be solved by using other molecules,
such as antibodies. "But the challenge is how get
these large proteins into the cell," continues Pei.
A technique that provides a more general solution,
and is used extensively in Pei's group, involves the
use of macrocycles such as macrocyclic peptides,
"which have a lot of advantages over other
approaches and, in addition, they are smaller than
proteins and easier to make," says Pei.

When small molecules interact with a flat
protein-protein interface, as opposed to a
protein binding pocket, one of the most critical
aspects revolves around how many points of
contact are being lost, because this leads to
the loss of binding energy and to an exponential loss of the binding affinity. "And
that is where small molecules get
into trouble, because they don't
have enough binding affinity,"
says Pei.
Macrocycles that are 3-5 times
larger than conventional smallmolecule drugs, due to their ability
to make multiple points of contact
with flat surfaces, can compete with
proteins for target binding and yet
retain several physicochemical characteristics of small molecules. "Because the molecule
is larger, it has a larger interface and more points
of contact, and that is the idea behind using
macrocycles," says Pei.
Getty Images / LAGUNA DESIGN

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