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Design of Complement Inhibitors for Cardiovascular Disease

Institution: University of California, Riverside
Investigator(s): Dimitrios Morikis, Ph.D.
Award Cycle: 2011 (Cycle 20) Grant #: 20XT-0005 Award: $250,000
Subject Area: Cardiovascular Disease
Award Type: Exploratory/Developmental Award

Initial Award Abstract
The abdominal aortic aneurysm (AAA) is a pathologic dilatation of the aorta, which is responsible for numerous hospitalizations and open-heart repairs, and several thousands of deaths every year in the United States. It has been shown that age, gender, and use of tobacco are the most significant risk factors for AAA. Our goal is to develop potential therapeutics for AAAs. We are targeting the ability of the immune system to recruit white blood cells to the aortic wall, a process that is associated to AAA, through the involvement of the proinflammatory protein C5a. Our drug design strategy is based on the native mechanism of the interaction between C5a and its cell membrane-bound receptor, C5aR, to develop peptidic, peptidomimetic, and chemical compound inhibitors. Our design methods involve in silico structural modeling, structural and physicochemical analyses, virtual screening, in vitro assays with polymorphonuclear leukocytes, and an in vivo AAA mouse model. We have generated preliminary data which indicate that nicotine can exacerbate AAA development in preclinical models and we have preliminary designs of potential peptide inhibitors of the C5a-C5aR interaction. Data generated from these studies will provide us with potential therapeutics against AAA, will lay the groundwork for several avenues of research on the mechanistic aspects of complement system inhibition, and will add to our understanding of how tobacco use enhances AAA disease. We expect that our research will present a paradigm for the synergy between in silico, in vitro, and in vivo studies applied in drug discovery and will make significant contributions in rapid translation of basic research to the clinical setting.