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Novel drug candidates offer new route to controlling inflammation
Date:5/14/2012

e 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 cand
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Contact: Steven Schultz
sschultz@princeton.edu
609-252-1919
Princeton University, Engineering School
Source:Eurekalert  

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