Complement is an immune effector system present in blood that functions to protect the body against microorganisms, but in situations of dysregulation, complement participates in a variety of pathologies inclusive of age-related macular degeneration, multiple sclerosis, Guillain-Barr syndrome, arthritis, and hemolytic anemias. However, to date only one complement therapeutic, Eculizumab, a mAb directed against C5, has attained FDA approval to treat hemolytic anemias. Accordingly, there is a pressing need for effective therapeutics that can tame aberrant complement inflammation and membranolysis in a variety of disorders. Given the diversity of complement mediated pathologies, an arsenal of therapeutic strategies requires development. Molecular targets to control unwanted complement activation currently under development include those to C3 and C5, which act pivotally in the pathways. C5 is of particular interest to us because activation results in the release of the inflammatory peptide C5a, and a larger fragment C5b that initiates the formation of the Membrane Attack Complex, which damages target membranes. Furthermore, we have experience investigating many functional and structural aspects of C5;therefore, we are well positioned to focus at C5 for discovery of specific inhibitors. For this purpose, assays are being developed that are suitable for screening chemical libraries in order to identify probes that antagonize C5 interactions. These include three sets of binding assays to measure C5 interactions, namely the reversible interaction with C3b, the reversible interaction with C6 and C7, and the irreversible binding to C6. These assays are suitable for medium (Aim 1) and high throughput screening (Aim 2). The plan is to screen initially combinatorial peptide libraries from the Torrey Pines Institute for Molecular Studies (Aim 3). These are a unique resource that were developed at this Institute, and are constituted by millions of entries. If the screening succeeds and yields inhibitory peptides that are specific, this would constitute the initial step of a long range project to discover new agents that can therapeutically intervene in pathological situations in which uncontrolled complement activation occurs.
Complement is a constituent of the immune system that has evolved to protect the body against microorganisms;however, in uncontrolled situations, complement can contribute to autoimmune diseases and inflammation. The proposed research is focused at attaining chemical compounds that may be starting ingredients for the development of new drugs that may find application for complement inhibition in situations where this immunity mechanism is harming the host. Examples of diseases that could have an improved outcome if effective new medicines were developed that could with safety and specificity inhibit undesired complement activation are hemolytic anemias, multiple sclerosis, Guillain-Barr syndrome, and arthritis.
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