Cisbio eBook - 23

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

Biosciences, and associate adjunct professor of
medicine at University of California, San Diego.
Aβ, the major neurotoxic agent in Alzheimer's
disease, and the main component of the amyloid
plaques that are found in the brains of patients
with Alzheimer's disease, is formed by the
sequential cleavage of the amyloid precursor
protein (APP) by β- and γ-secretases. Inhibiting
the catalytic activity of either of the two enzymes
inhibits the release of the Aβ peptide.
"However, each of these enzymes has 50-60
different substrates besides APP, and inhibiting
these reactions, some of which are incredibly
important to the cell, gives rise to many off-target
effects," says Dr. Dewji. For example, γ-secretase
also catalyzes the release of the intracellular
domain of Notch, which subsequently translocates into the nucleus to bind transcription
factors and modulate gene expression. While
most of the γ-secretase inhibitors designed for

Alzheimer's disease have failed, some of the
β-secretase inhibitors, which have fewer adverse
effects, are still being pursued.
"Our approach uses peptides that are derived
from presenilin-1 (PS-1), which is one of the
components of the γ-secretase complex," says
Dr. Dewji. The technology that Dr. Dewji and
colleagues use is based on their observation
that binding of a fragment of the amino terminal
domain of PS-1 to APP can inhibit the production
of Aβ. This binding to APP occurs at a location
that is away from the β- and γ-secretase
cleavage sites.

reduced Aβ levels in vitro and in transgenic
mice by 50-70%. "We are moving
forward with the development of
this peptide," Dr. Dewji declares.
"Early next year we hope
to start Phase I

"This approach is incredibly specific,"
asserts Dr. Dewji, who adds that the catalytic activities of the enzymes are "not
targeted and remain intact." Using the
lead candidate peptide, investigators at Cenna Biosciences

Amino acids, such as this aspartic acid molecule, are the building blocks for peptide therapeutics that
many drug developers see as the future for clinical medicine. Atoms are represented as spheres and are
colour-coded: carbon (grey), hydrogen (blue-green), nitrogen (blue) and oxygen (red).

23 |

Getty Images / Science Photo
Library / PASIEKA

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