Cisbio eBook - 19

Trends in Protein-Protein Interactions Research | Advantages May Place Peptides Ahead of Small-Molecule Drugs

overcome the limitations of naturally occurring peptides, which include low bioavailability,
physical and chemical instability, low membrane
permeability, short half-life, and fast elimination. A peptide's limitations may be addressed
via chemical modifications, but such modifications shouldn't attenuate the peptide's strengths,
which include specificity, potency, safety,
predictable metabolism, and ease of synthesis.
This is a balancing act, and it is performed not
only for modified versions of natural peptides,
but also for peptides that possess novel structures, or are abstracted or excerpted from larger

Permeability First
"We are focused on targeting intracellular
protein-protein interactions that are key drivers
in oncology pathways," says David J. Earp, Ph.D.,
president and CEO of Circle Pharma. Research at
Circle Pharma is focusing on macrocycles, which
are cyclic molecules of at least 12 atoms and are
favorably positioned for targeting protein interfaces that are difficult to interrogate.

19 |

The polar surface areas of macrocycles, however,
present challenges with respect to cell permeability and oral bioavailability. "We found a very
good solution for the permeability issue," asserts
Dr. Earp, who observes that poor permeability is
common problem in the development of macrocycle drugs.

chemokine receptor clinically attractive for applications that include oncology and autoimmune,
metabolic, and infectious diseases. This work
originated from previous research that found a
hexamer peptide macrocycle with modest CXCR7
binding affinity and no measurable cell permeability (and therefore no oral bioavailability).

The discovery platform at Circle Pharma
combines automated synthetic chemistry
with computational permeability design and
medicinal chemistry-oriented structure-based
drug design for peptide-peptoid hybrid macrocycles. "What makes our platform attractive is
that permeability is the very first thing that we
build into the design process, and therefore it
is not something that we have to solve later on
during development," explains Dr. Earp, "and the
peptoids in our macrocycles enable wide chemical diversity, well beyond peptide macrocycles."

"Using our computational design platform,
we created cell-permeable derivatives of that
initial macrocycle," notes Dr. Earp. "By incorporating and exploiting peptoids, we were able to
achieve 500-fold improvement in target affinity."
In rodent studies administered by Pfizer, one
of these compounds, demonstrated 18% oral

In a recent collaboration with Pfizer, Circle
Pharma developed a potent and orally bioavailable macrocyclic peptide targeting CXCR7, a

"In addition to creating derivatives of the initial
macrocycle, we also successfully scaffold-hopped,
screening our large virtual libraries to identify
new scaffolds with good permeability characteristics and target fit," continues Dr. Earp. "We then
advanced affinity using structure-based medicinal chemistry."

Cisbio eBook

Table of Contents for the Digital Edition of Cisbio eBook

Cisbio eBook - 1
Cisbio eBook - 2
Cisbio eBook - 3
Cisbio eBook - Contents
Cisbio eBook - 5
Cisbio eBook - 6
Cisbio eBook - 7
Cisbio eBook - 8
Cisbio eBook - 9
Cisbio eBook - 10
Cisbio eBook - 11
Cisbio eBook - 12
Cisbio eBook - 13
Cisbio eBook - 14
Cisbio eBook - 15
Cisbio eBook - 16
Cisbio eBook - 17
Cisbio eBook - 18
Cisbio eBook - 19
Cisbio eBook - 20
Cisbio eBook - 21
Cisbio eBook - 22
Cisbio eBook - 23
Cisbio eBook - 24
Cisbio eBook - 25
Cisbio eBook - 26
Cisbio eBook - 27
Cisbio eBook - 28
Cisbio eBook - 29
Cisbio eBook - 30
Cisbio eBook - 31