Cisbio eBook - 25

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

those molecules were changing, and which of the
peptide combinations would cure diabetes," says
Dr. Rondinone.

glucose homeostasis), as well glucagon's benefits
(on lipids and body weight). This is how our
molecule was born," says Dr. Rondinone.

Scientists at MedImmune interrogated combinations of peptides and hormones and identified a
peptide dual agonist of glucagon-like peptide-1
(GLP-1) and glucagon receptors. The peptide dual
agonist mimics the effects of oxyntomodulin, a
glucose- and appetite-regulating gut hormone.
In patients with type 2 diabetes, the secretion of
oxyntomodulin is significantly impaired, and after
gastric bypass surgery, the oxyntomodulin level
is increased by more than 10-fold.

A key component of this work involved peptide
chemistry to develop and modify the peptides
to make them more potent and extend their
half-lives. For example, coupling to palmitic
acid facilitated the reversible binding of the
lead peptide to albumin and extended its
plasma half-life.

The scientists reasoned that a modified version of
oxyntomodulin might have therapeutic potential
against obesity and diabetes. "We synthesized
more than 500 peptides and changed the ratio
between the GLP-1 and the glucagon receptor
agonism," details Dr. Rondinone. This work, he
continues, "helped us find the ideal peptide," that
is, one capable of combining GLP-1's benefits (on

25 |

Using systems biology data modeling and pharmacokinetic and pharmacodynamics screenings
in animal models, Dr. Rondinone and colleagues
selected MEDI0382 for clinical studies. MEDI0382
showed robust anti-obesity and metabolic effects in
mice and nonhuman primates, and a randomized,
double-blind, placebo-controlled Phase II trial on
overweight and obese adults with type 2 diabetes
mellitus is underway. "We have other peptides in
our pipeline that might be beneficial for other indications apart from diabetes," adds Dr. Rondinone. n

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