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, 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 256 times. This proposal has three 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 human-mouse chimeric C3 will be generated to assess Compstatin's activity in the in vivo models proposed in Projects 1 and 2.
In Aim 2, phage peptide libraries will be screened to identify complement inhibitors targeting factor B, *MASP2* *, C3, and C1.
In Aim 3, in silico screening methodologies utilizing public and commercial compound libraries will be applied to identify compounds targeting C3, factor B, *MASP2* *, and C1.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI068730-05
Application #
8321596
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$349,743
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Mastellos, Dimitrios C; Reis, Edimara S; Yancopoulou, Despina et al. (2018) Expanding Complement Therapeutics for the Treatment of Paroxysmal Nocturnal Hemoglobinuria. Semin Hematol 55:167-175
Reis, Edimara S; Mastellos, Dimitrios C; Ricklin, Daniel et al. (2018) Complement in cancer: untangling an intricate relationship. Nat Rev Immunol 18:5-18
Sauter, Reinhard J; Sauter, Manuela; Reis, Edimara S et al. (2018) Functional Relevance of the Anaphylatoxin Receptor C3aR for Platelet Function and Arterial Thrombus Formation Marks an Intersection Point Between Innate Immunity and Thrombosis. Circulation 138:1720-1735
Reis, Edimara S; Berger, Nadja; Wang, Xin et al. (2018) Safety profile after prolonged C3 inhibition. Clin Immunol 197:96-106
Laabei, Maisem; Liu, Guanghui; Ermert, David et al. (2018) Short Leucine-Rich Proteoglycans Modulate Complement Activity and Increase Killing of the Respiratory Pathogen Moraxella catarrhalis. J Immunol 201:2721-2730
Huber-Lang, Markus; Lambris, John D; Ward, Peter A (2018) Innate immune responses to trauma. Nat Immunol 19:327-341
Chen, Lan-Sun; Kourtzelis, Ioannis; Singh, Rashim Pal et al. (2018) Endothelial Cell-Specific Overexpression of Del-1 Drives Expansion of Haematopoietic Progenitor Cells in the Bone Marrow. Thromb Haemost :
Lamont, Richard J; Koo, Hyun; Hajishengallis, George (2018) The oral microbiota: dynamic communities and host interactions. Nat Rev Microbiol 16:745-759
Bostanci, Nagihan; Bao, Kai; Li, Xiaofei et al. (2018) Gingival Exudatome Dynamics Implicate Inhibition of the Alternative Complement Pathway in the Protective Action of the C3 Inhibitor Cp40 in Nonhuman Primate Periodontitis. J Proteome Res 17:3153-3175
Ricklin, Daniel; Mastellos, Dimitrios C; Reis, Edimara S et al. (2018) The renaissance of complement therapeutics. Nat Rev Nephrol 14:26-47

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