International Team of Researchers Designs Peptides Targeting Inflammation
|Posted May 14, 2012|
A cross-disciplinary collaboration among four research teams from three continents has developed novel peptides that have the potential to treat diseases involving inflammation, such as asthma, rheumatoid arthritis, stroke, reperfusion injuries, and sepsis. This work is reported in a recent research article published in the Journal of Medicinal Chemistry (issue of May 10,2012).
The peptides target the innate immune system receptor C3aR, a G protein-coupled receptor, which upon binding with its native ligand C3a modulates inflammatory responses. C3a has dual and opposing roles in promoting or suppressing inflammation, depending on the cellular system, making the development of C3aR agonists and antagonists of interest in drug design for regulation of inflammation. Perhaps because of this complexity, C3aR has proved to be a very difficult drug target and so these new peptides will be an important addition to the research ‘toolkit’ that we need to facilitate the development of new anti-inflammatory drugs.
The collaboration includes Christodoulos Floudas, Stephen C. Macaleer ’63 Professor of Engineering and Applied Science, Professor of Chemical and Biological Engineering of Princeton University, Dimitrios Morikis, Professor of Bioengineering, University of California, Riverside, Dr. Peter Monk of the Department of Infection and Immunity, University of Sheffield Medical School, UK, and Dr. Trent Woodruff of the School of Biomedical Sciences, University of Queensland, Australia.
Professor Floudas and his graduate students Meghan Bellows-Peterson and Ho Ki Fung have introduced and applied a novel computational framework for de novo peptide and protein design, to design numerous peptide sequences with predicted affinity for binding to C3aR. This is a first-principles predictive framework for the determination of amino acid sequences that are energetically favorable in a given three-dimensional flexible template structure. Professor Morikis and his graduate students Chris Kieslich and Li Zhang provided three-dimensional structures of C3a, the native ligand of C3aR. The flexible templates were produced by molecular dynamics simulations, from which several snapshots of the last 15 amino acids were selected as flexible templates for the de novo design. Drs. Monk and Woodruff joined the long-term collaboration of Professors Floudas and Morikis to perform experimental testing of the de novo designed peptides. Using a degranulation assay in rat cells (Monk and his Postdoctoral Fellow Kathryn Wareham) and a calcium flux assay in human cells (Woodruff and his student Owen Hawksworth), they demonstrated that two peptides were potent full C3aR agonists, whilst two others were partial agonists, that displayed full antagonist activity in a C3aR activation assay. The Morikis group also provided physicochemical analysis of the sequences that implicates the spatial distribution of the electrostatic potential of the peptides in discriminating agonist from partial agonist/antagonist activity.
These results are promising as they demonstrate the design of two of the most potent C3aR agonists known today (at nanomolar range), and the development of the first peptide-based partial C3a agonists. The researchers plan to test the de novo peptides in animal models for further characterization and potential for therapeutic intervention to treat specific inflammatory and autoimmune diseases. They are also interested to further explore the mechanism of the dual role of C3a in inflammation, and to further develop and test novel inhibitors of the complement inflammatory cascade.