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 objective is to deterxnine 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 Y.PLOR. To understand the mechanism of action, we plan to improve the initial map by using phase combination (of the molecular replacement and multiple isomorphous replacement phases), build the Factor D model, and refine the structure and characterize the active site. The long-term goal in Phase II is to design and synthesize specific inhibitors for Factor D using a structure-based drug design process.Awardee's statement of the potential commercial applications of the research:Factor D inhibitors have potential therapeutic application for the approximately 1. 5 million new ARDS patients every year, for Coronary Artery Disease patients, and in the treatment of autoimmune diseases.National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
