Recent experimental findings by the Kelly and Balch groups indicate that the proprotein convertase furin is responsible for the first proteolytic cleavage event in the DI 87N and DI 87Y mutants of gelsolin. A second proteolysis results in the 172-243 fragment responsible for fibril deposition in Familial Amyloidosis of the Finnish type (FAF). Furin is believed to be involved in the processing of consitutively secreted precursors to peptidyl hormones, plasma proteins, bacterial exotoxins, viral envelope glycoproteins, receptors, matrix metalloproteinases, and growth factors. Therefore, furin has become an important therapeutic target. A fluorescence-based screen to identify small molecule lead compounds for furin inhibitor methods will be employed. Currently there are no known crystal structures available for any member of the furin family of convertases. Crystal structures of furin-inhibitor complexes will be obtained for x-ray crystallography studies. These 3-dimensional structures will then be used as a starting point for structure based design of more potent inhibitors. Inhibition constants for furin inhibitors will be determined through spectrofluorometric methods.
| Green, Nora S; Foss, Ted R; Kelly, Jeffery W (2005) Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis. Proc Natl Acad Sci U S A 102:14545-50 |
| Wiseman, R Luke; Green, Nora S; Kelly, Jeffery W (2005) Kinetic stabilization of an oligomeric protein under physiological conditions demonstrated by a lack of subunit exchange: implications for transthyretin amyloidosis. Biochemistry 44:9265-74 |
| Green, Nora S; Palaninathan, Satheesh K; Sacchettini, James C et al. (2003) Synthesis and characterization of potent bivalent amyloidosis inhibitors that bind prior to transthyretin tetramerization. J Am Chem Soc 125:13404-14 |
