Complement is important in physiology, but it is also a pathogenic factor in a large number ofinflammatory diseases. Complement-mediated tissue injury has been reported in a wide variety ofdisorders, including but not limited to autoimmune diseases, adult respiratory distress syndrome,Alzheimer's disease, stroke, heart attack, burn injuries, organ transplantation, as well as inextracorporeal blood oxygenation. There is a critical need for a therapeutically applicablecomplement inhibitor. Several complement inhibitors have been described; however, the lowmolecular weight inhibitors designed in the past showed low activity and high toxicity and aretherefore pharmacologically undesirable. Recombinant forms of complement regulatory proteinssuch 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 molecularweight proteins and require intravenous administration; also, most of them have only a short half-lifein vivo. Recent studies have focused on a second generation of low molecular weight derivativeswith 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 theclassical, lectin, and alternative pathways. This peptide effectively inhibits complement activation inclinically relevant in vitro, ex vivo and, most importantly, in vivo models. The activity of the parentpeptide has now been improved 256 times. This proposal has three aims:
In Aim 1, a) the in vivoactivity of the most potent Compstatin analogs will be assessed, b) their in vivo efficacy will beimproved, and c) a mouse transgenic model using a human-mouse chimeric C3 will be generated toassess Compstatin's activity in the in vivo models proposed in Projects 1 and 2.
In Aim 2, phagepeptide 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 compoundlibraries will be applied to identify compounds targeting C3, factor B, *MASP2* *, and C1.
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