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In search of a complement system inhibitor targeting C5aR

Institution: University of California, Riverside
Investigator(s): Chris Kieslich, B.S. in Biomedical Engineering
Award Cycle: 2010 (Cycle 19) Grant #: 19DT-0011 Award: $60,000
Subject Area: General Biomedical Science
Award Type: Dissertation Awards
Abstracts

Initial Award Abstract
The importance of understanding the regulation and activation of the complement immune system to cardiovascular research has been evident since the late 1970’s, when changes in serum complement were observed in patients who received extracorporeal circulation. In the decades since this initial discovery, researchers have found that complement-mediated inflammation is involved in pathologies such as ischemia-reperfusion injury, atherosclerosis, and abdominal aortic aneurism. Complement-mediated inflammation is achieved through the anaphylatoxins, complement fragments C3a and C5a, whose primary functions are the chemotaxis and activation of leukocytes. The anaphylatoxins achieve their pro-inflammatory activity through activation of their specific receptors C3aR and C5aR; both receptors belong to the G-protein coupled receptor (GPCR) super family and both are expressed on a wide range of inflammatory cells.

Extensive research has been devoted to the development of agonists/antagonists targeting the anaphylatoxin receptors, however there is no such therapeutic in use in the clinic today. Low molecular mass C5aR-inhibitors could have great potential both as a therapeutic for cardiovascular disease, as well as, an investigative tool for understanding the role of C5a in various cardiovascular pathologies. Therefore, the proposed studies will utilize computational methods to search for low molecular weight inhibitors of C5aR. A computational model of C5a bound to C5aR in explicit water and membrane will first be developed and evaluated in view of available experimental data. Subsequently, the developed model will be used in search a database of drug-like molecules targeting C5aR. Finally, experimental assays will be used to test the predicted ligands.
Publications

Exploring protein-protein and protein-ligand interactions in the immune system using molecular_x000D_ dynamics and continuum electrostatics
Periodical: Current Physical Chemistry Index Medicus:
Authors: Kieslich, C.A.*, Tamamis, P*, Gorham, R.D., López de Victoria, A., Sausman, N.U., Archonti ART
Yr: 2012 Vol: 2 Nbr: Abs: Pg: 324-343

Molecular similarity determination using multi-resolution analysis
Periodical: Molecular Informatics Index Medicus:
Authors: Hakkoymaz, H., Kieslich, C.A., Gorham, R.D., Gunopulos, D., and Morikis, D. ART
Yr: 2011 Vol: 30 Nbr: 8 Abs: Pg: 733-46