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

Abstracts

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.

Publications

Derivation of ligands for the complement C3a receptor from the_x000D_ C-terminus of C5a
Periodical: European Journal of Pharmacology			Index Medicus:
Authors: Halai R, Bellows-Peterson ML, Branchett, W, Smadbeck J, Kieslich CA, Croker DE, Cooper MA,				ART
Yr:	Vol:	Nbr:	Abs:	Pg:

Insights into the mechanism of C5aR inhibition by PMX53 via implicit solvent molecular dynamics simulations and docking
Periodical: BMC Biophysics			Index Medicus:
Authors: Tamamis P, Kieslich CA, Nikiforovich GV, Woodruff TM, Morikis D, Archontis G				ART
Yr: 2014	Vol: 7	Nbr: 5	Abs:	Pg:

De novo peptide design with C3a receptor agonist and antagonist activities: theoretical predictions and experimental validation
Periodical: Journal of Medicinal Chemistry			Index Medicus:
Authors: Bellows-Peterson ML, Fung H, Floudas CA, Kieslich CA, Zhang L, Morikis D, Wareham KJ, Monk				ART
Yr: 2012	Vol: 55	Nbr:	Abs:	Pg: 4159-4168

Exploring protein-ligand and protein-protein interactions in the immune system using molecular dynamics andcontinuum electrostatics_x000D_ continuum electrostatics
Periodical: Current Physical Chemistry			Index Medicus:
Authors: Kieslich CA, Tamamis P, Gorham RD Jr, López de Victoria A, Sausman N, Archontis G, Morikis				ART
Yr: 2012	Vol: 2	Nbr:	Abs:	Pg: 324-343

Discovery of novel selective C5a2 ligands that can modulate IL-6 release from macrophages
Periodical: Cytokine			Index Medicus:
Authors: Croker DE, Halai R, Kaeslin G, Morikis D, Woodruff TM, Floudas CA, Monk PN, Cooper MA				ABS
Yr: 2014	Vol: 70	Nbr:	Abs:	Pg: 28-79

Derivation of ligands for the complement C3a receptor from the_x000D_ C-terminus of C5a
Periodical: European Journal of Pharmacology			Index Medicus:
Authors: Halai R, Bellows-Peterson ML, Branchett, W, Smadbeck J, Kieslich CA, Croker DE, Cooper MA,				ART
Yr:	Vol:	Nbr:	Abs:	Pg:

Insights into the mechanism of C5aR inhibition by PMX53 via implicit solvent molecular dynamics simulations and docking
Periodical: BMC Biophysics			Index Medicus:
Authors: Tamamis P, Kieslich CA, Nikiforovich GV, Woodruff TM, Morikis D, Archontis G				ART
Yr: 2014	Vol: 7	Nbr: 5	Abs:	Pg:

De novo peptide design with C3a receptor agonist and antagonist activities: theoretical predictions and experimental validation
Periodical: Journal of Medicinal Chemistry			Index Medicus:
Authors: Bellows-Peterson ML, Fung H, Floudas CA, Kieslich CA, Zhang L, Morikis D, Wareham KJ, Monk				ART
Yr: 2012	Vol: 55	Nbr:	Abs:	Pg: 4159-4168

Exploring protein-ligand and protein-protein interactions in the immune system using molecular dynamics andcontinuum electrostatics_x000D_ continuum electrostatics
Periodical: Current Physical Chemistry			Index Medicus:
Authors: Kieslich CA, Tamamis P, Gorham RD Jr, López de Victoria A, Sausman N, Archontis G, Morikis				ART
Yr: 2012	Vol: 2	Nbr:	Abs:	Pg: 324-343

Discovery of novel selective C5a2 ligands that can modulate IL-6 release from macrophages
Periodical: Cytokine			Index Medicus:
Authors: Croker DE, Halai R, Kaeslin G, Morikis D, Woodruff TM, Floudas CA, Monk PN, Cooper MA				ABS
Yr: 2014	Vol: 70	Nbr:	Abs:	Pg: 28-79