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!
Team discovers how bacteria exploit a chink in the body's armor
20.01.2017 | University of Illinois at Urbana-Champaign
Rabies viruses reveal wiring in transparent brains
19.01.2017 | Rheinische Friedrich-Wilhelms-Universität Bonn
An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
19.01.2017 | Event News
10.01.2017 | Event News
09.01.2017 | Event News
20.01.2017 | Awards Funding
20.01.2017 | Materials Sciences
20.01.2017 | Life Sciences