The long-term goal of this program is to develop small molecule inhibitors of complement for clinical use. Complement in the human bloodstream plays a key role in the body's response to invasion by foreign cells. While complement deficiency can lead to recurrent infections and autoimmune diseases, inappropriate and uncontrolled complement activation can be harmful as well, contributing to many acute and chronic inflammatory conditions including ischemia/reperfusion injury, rheumatoid arthritis, and Alzheimer's disease. Complement components C3 and C5 occupy focal points in the complement cascade, and all current commercial efforts to develop anti-complement drugs are therefore directed at one of these two proteins. They recently identified a binding site in C5 that is essential for transient recognition by the protease responsible for activating C5. They then used the sequence of this binding site to design an interface peptide that blocks C5 binding to the protease. In this application, they propose to use conventional peptide synthesis and modification methods to systematically alter the structure of this peptide to improve its activity as a complement inhibitor. Development of a more potent derivative may lead directly to a clinically useful small molecule anticomplement drug.
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