STRUCT.-BASED DESIGN OF INHIB. FOR COMPLEMENT PROTEIN D

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DESCRIPTION: (Adapted from the Applicants Abstract). Complement protein Factor D plays an important role in the alternative pathway of the complement system. Inhibitors for Factor D have potential application in the treatment of adult respiratory syndrome (ARDS) and autoimmune diseases such as rheumatoid arthritis. The Phase I aim of this proposal is to determine the three-dimensional structure of Factor D by X-ray crystallographic methods. Diffraction data for native crystals and two potential heavy atom derivatives are in hand. A molecular replacement solution has been obtained using the structure of the homologous serine protease, rat mast cell protease. This model has been refined to an R- value of 0.21, using XPLOR. The investigators plan to improve the initial map by using phase combination (of the molecular replacement and multiple isomorphous replacement phases); build the Factor D model; refine the structure and characterize the active site to understand the mechanism of action. The long term goal in Phase II is to design and synthesize specific inhibitors for Factor D using a structure-based drug design process.