Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Novel drug candidates offer new route to controlling inflammation

15.05.2012
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.

The work was funded in part by the National Science Foundation, National Institutes of Health, University of California Tobacco-Related Disease Research Program, Beckman Initiative for Macular Research, US Environmental Protection Agency, British Heart Foundation, and the US Department of Defense. Further details are available here: http://titan.princeton.edu/news/ournews/?name=DesignPeptideInflam

Steven Schultz | EurekAlert!
Further information:
http://www.princeton.edu

More articles from Health and Medicine:

nachricht Cystic fibrosis alters the structure of mucus in airways
28.06.2017 | University of Iowa Health Care

nachricht Mice provide insight into genetics of autism spectrum disorders
28.06.2017 | University of California - Davis

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Supersensitive through quantum entanglement

28.06.2017 | Physics and Astronomy

X-ray photoelectron spectroscopy under real ambient pressure conditions

28.06.2017 | Physics and Astronomy

Mice provide insight into genetics of autism spectrum disorders

28.06.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>