Navigation Links
Novel drug candidates offer new route to controlling inflammation

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.


Contact: Steven Schultz
Princeton University, Engineering School

Related medicine news :

1. Rutgers team discovers novel approach to stimulate immune cells
2. Novel compound demonstrates anti-leukemic effect in zebrafish, shows promise for human treatment
3. Novel drug in pill form safer than standard approach to treat blocked lung blood vessels
4. Novel mouse model for autism yields clues to a 50-year-old mystery
5. Unprecedented academic-industry collaboration seeks new drugs and novel treatments for autism
6. Novel plastics and textiles from waste with the use of microbes
7. UC San Diego among first in nation to treat brain cancer with novel viral vector
8. Students at Western University develop a novel way to teach interdisciplinary care
9. UH Case Medical Center publishes study on novel treatment for skin lymphoma
10. Mass. General researchers find novel way to prevent drug-induced liver injury
11. Rutgers, Massachusetts General investigators find novel way to prevent drug-induced liver injury
Post Your Comments:
Related Image:
Novel drug candidates offer new route to controlling inflammation
(Date:6/27/2016)... ... June 27, 2016 , ... ... payment industry today announced its strategic partnership with Connance, a healthcare industry ... The two companies’ proven, proprietary technology combine to provide health systems, hospitals ...
(Date:6/26/2016)... , ... June 26, 2016 , ... On June 10-11, ... of the 2016 Cereal Festival and World’s Longest Breakfast Table in Battle Creek, MI, ... the city’s history as home to some of the world’s leading providers of cereal ...
(Date:6/26/2016)... ... June 26, 2016 , ... Many ... been diagnosed with endometriosis. These women need a treatment plan to not only ... approach that can help for preservation of fertility and ultimately achieving a pregnancy. ...
(Date:6/25/2016)... ... June 25, 2016 , ... "With 30 hand-drawn hand gesture animations, FCPX ... Austin - CEO of Pixel Film Studios. , ProHand Cartoon’s package transforms over ... Cut Pro X . Simply select a ProHand generator and drag it above media ...
(Date:6/25/2016)... ... June 25, 2016 , ... On Friday, June 10, ... Bronze Wellness at Work award to iHire in recognition of their exemplary accomplishments in ... the 7th annual Maryland Workplace Health & Wellness Symposium at the BWI Marriott in ...
Breaking Medicine News(10 mins):
(Date:6/23/2016)... Research and Markets has announced the addition of ... their offering. The current ... environment for MedImmune to enter. The US ageing population creates ... drive considerable growth for effective anti-influenza medications. The introduction of ... but development is still in its infancy. ...
(Date:6/23/2016)... and BOGOTA, Colombia , June 23, 2016  Astellas today announced the establishment of ... Farma Brasil as the company,s second affiliate in Latin America . ... ... Manager of Astellas Farma Colombia ... ...
(Date:6/23/2016)... 2016 Research and Markets has ... Global Analysis (United States, China, Japan, Brazil, United Kingdom, ... their offering. Surgical ... business planners, provides surgical procedure volume data in a ... an in-depth analysis of growth drivers and inhibitors, including ...
Breaking Medicine Technology: