An international team created drug candidates
based on the naturally occurring C3a peptide, the chain of molecules shown
here. The C3a peptide is a key player in regulating immune responses and drugs
that enhance or block its effects could be useful in treating many inflammatory
diseases. Credit: Journal of Medicinal Chemistry
Pursuing a relatively untapped route for
regulating the immune system, an international team of researchers has designed
and conducted initial tests on molecules that have the potential to treat
diseases involving inflammation, such as asthma, rheumatoid arthritis, stroke
and sepsis.
The
team started by creating a three-dimensional map of a protein structure called
the C3a receptor, which sits on the surface of human cells and
plays a critical role in regulating a branch of the immune system called
the complement system.
They
then used computational
techniques to design short portions of protein molecules,
known as peptides, that they predicted would interact with the receptor and
either block or enhance aspects of its activity. Finally, experimentalists
validated the theoretical
predictions by synthesizing the peptides and testing them in animal
and human cells.
The
researchers – a collaboration of teams at four institutions on three continents
– published their results May 10 in the Journal of
Medicinal Chemistry.
The
collaboration includes Christodoulos Floudas, the Stephen C. Macaleer '63
Professor of Engineering and Applied Science in the Department of Chemical and
Biological Engineering at Princeton University; Dimitrios Morikis, professor of
bioengineering at the University of California, Riverside; Peter Monk of the
Department of Infection and Immunity at the University of Sheffield Medical
School, U.K.; and Trent Woodruff of the School of Biomedical Sciences at the
University of Queensland, Australia.
The
regulation of the complement system – so called because it complements the
body's central system of immune cells and antibodies – is thought to be a
possible route to controlling over-active or mistaken immune responses that
cause damage. However, few drugs directly target complement proteins, and none
targets the C3a receptor, in part because of the complexity of the complement
system. In some cases complement activity can help downplay immune responses while
in other cases it can stoke even stronger reactions.
The
collaborators were able to create peptides that blocked activity of C3a
(antagonists) and others that stimulated it (agonists) with unprecedented
potency and precision. Their success stems from a novel optimization-based
approach, developed in the Floudas lab, for computing how a protein's
three-dimensional structure will change when changes are made in the protein's
chemical sequence. This ability to design peptides of a desired shape, allowed them
to target the C3a receptor in precise ways.
Morikis
and his graduate students Chris Kieslich and Li Zhang provided the
collaborators the 3D structure of the naturally occurring peptide that normally
regulates the C3a receptor in human cells. Using a portion of that structure as
a flexible template, Floudas and graduate students Meghan Bellows-Peterson and
Ho Ki Fung designed new peptides that were predicted either to enhance or block
C3a. Monk and postdoctoral fellow Kathryn Wareham tested the predictions in rat
cells, while Woodruff and student Owen Hawksworth tested them in human cells.
Among
the conditions potentially treatable through complement regulation is
reperfusion injury, which occurs when blood flow is temporarily cut off to some
part of the body, as in a heart attack or stroke, and then an inflammatory
response develops when the blood returns. Another possible use would be in
organ transplantation, in which the body often mounts a destructive immune
response against the newly introduced organ. Other common conditions affected
by the complement system are rheumatoid arthritis and sepsis.
As next
steps, the team will seek to test their peptides in live animal
models of inflammation. They also plan to explore more generally the dual role
of C3a in inflammation,
with an eye toward developing further drug candidates.
Provided
by Princeton University, Engineering School
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