Complement is important in physiology, but it is also a pathogenic factor in a large number of inflammatory diseases. Complement-mediated tissue injury has been reported in a wide variety of disorders, including but not limited to autoimmune diseases, adult respiratory distress syndrome, Alzheimer's disease, stroke, heart attack, burn injuries, age related macular degeneration, organ transplantation, as well as in extracorporeal blood oxygenation. There is a critical need for a therapeutically applicable complement inhibitor. Several complement inhibitors have been described;however, the low molecular weight inhibitors designed in the past showed low activity and high toxicity and are therefore pharmacologically undesirable. Recombinant forms of complement regulatory proteins such as CR1, DAF, MCP, and CD59, and a monoclonal antibody against C5, have shown promise, as they have been effective in disease models. All these inhibitors, however, are large molecular weight proteins and require intravenous administration;also, most of them have only a short half-life in vivo. Recent studies have focused on a second generation of low molecular weight derivatives with more desirable properties, but none of these have yet been adopted as a therapeutic agent. We have taken the alternative approach of screening a peptide phage-display library for C3-interactive peptides and have isolated a novel small molecular weight cyclic peptide, Compstatin, which binds specifically to human and primate C3 and inhibits the activation of complement by the classical, lectin, and alternative pathways. This peptide effectively inhibits complement activation in clinically relevant in vitro, ex vivo and, most importantly, in vivo models. The activity of the parent peptide has now been improved 264 times. This proposal has two aims:
In Aim 1, a) the in vivo activity of the most potent Compstatin analogs will be assessed, b) their in vivo efficacy will be improved, and c) a mouse transgenic model using a mutated C3 will be generated to assess Compstatin's activity in in vivo mouse disease models.
In Aim 2, phage peptide libraries and in silico screening of public and commercial compound libraries will be used to identify complement inhibitors targeting factor B, factor D, C3, C5, and C1.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062134-07
Application #
7640634
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Marino, Pamela
Project Start
2001-03-01
Project End
2011-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
7
Fiscal Year
2009
Total Cost
$315,000
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Moll, Guido; Alm, Jessica J; Davies, Lindsay C et al. (2014) Do cryopreserved mesenchymal stromal cells display impaired immunomodulatory and therapeutic properties? Stem Cells 32:2430-42
Nilsson, Per H; Ekdahl, Kristina N; Magnusson, Peetra U et al. (2013) Autoregulation of thromboinflammation on biomaterial surfaces by a multicomponent therapeutic coating. Biomaterials 34:985-94
Landsem, A; Nielsen, E W; Fure, H et al. (2013) C1-inhibitor efficiently inhibits Escherichia?coli-induced tissue factor mRNA up-regulation, monocyte tissue factor expression and coagulation activation in human whole blood. Clin Exp Immunol 173:217-29
Qu, Hongchang; Ricklin, Daniel; Bai, Hongjun et al. (2013) New analogs of the clinical complement inhibitor compstatin with subnanomolar affinity and enhanced pharmacokinetic properties. Immunobiology 218:496-505
Brekke, O L; Waage, C; Christiansen, D et al. (2013) The effects of selective complement and CD14 inhibition on the E. coli-induced tissue factor mRNA upregulation, monocyte tissue factor expression, and tissue factor functional activity in human whole blood. Adv Exp Med Biol 735:123-36
Hajishengallis, George; Lambris, John D (2013) Complement-targeted therapeutics in periodontitis. Adv Exp Med Biol 735:197-206
Harboe, Morten; Garred, Peter; Lindstad, Julie K et al. (2012) The role of properdin in zymosan- and Escherichia coli-induced complement activation. J Immunol 189:2606-13
Hajishengallis, George; Lambris, John D (2012) Complement and dysbiosis in periodontal disease. Immunobiology 217:1111-6
Abe, Toshiharu; Hosur, Kavita B; Hajishengallis, Evlambia et al. (2012) Local complement-targeted intervention in periodontitis: proof-of-concept using a C5a receptor (CD88) antagonist. J Immunol 189:5442-8
Ricklin, Daniel (2012) Manipulating the mediator: modulation of the alternative complement pathway C3 convertase in health, disease and therapy. Immunobiology 217:1057-66

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