tailieunhanh - Báo cáo khoa học: Inhibition of amyloid fibrillation of lysozyme by indole derivatives ) possible mechanism of action

Amyloid aggregation of polypeptides is related to a growing number of pathologic states known as amyloid disorders. There is a great deal of interest in developing small molecule inhibitors of the amyloidogenic pro-cesses. | ỊFEBS Journal Inhibition of amyloid fibrillation of lysozyme by indole derivatives - possible mechanism of action Dina Morshedi1 Nasrollah Rezaei-Ghaleh1 Azadeh Ebrahim-Habibi1 Shahin Ahmadian1 and Mohsen Nemat-Gorgani1 2 1 Institute of Biochemistry and Biophysics University of Tehran Iran 2 Stanford Genome Technology Center Stanford University Palo Alto CA USA Keywords amyloid inhibition docking indole derivative lysozyme organic solvent Correspondence M. Nemat-Gorgani Stanford Genome Technology Center Stanford University 855 California Ave. Palo Alto CA 94304 USA Fax 1 650 812 1975 Tel 1 650 812 1961 E-mail mohsenn@ Received 21 August 2007 revised 10 October 2007 accepted 22 October 2007 doi Amyloid aggregation of polypeptides is related to a growing number of pathologic states known as amyloid disorders. There is a great deal of interest in developing small molecule inhibitors of the amyloidogenic processes. In the present article the inhibitory effects of some indole derivatives on amyloid fibrillation of hen egg white lysozyme HEWL are reported. Acidic pH and high temperatures were used to drive HEWL towards amyloid formation. A variety of techniques ranging from thioflavin T fluorescence and Congo red absorbance assays to far-UV CD and transmission electron microscopy were employed to characterize the HEWL fibrillation process. Among the indole derivatives tested indole 3-acetic acid indole 3-carbinol and tryptophol had the most inhibitory effects on amyloid formation indole and indole 3-propionic acid gave some inhibition and indole aldehyde and tryptophan showed no significant inhibition. Although indoles did not protect the HEWL native state from conformational changes they were effective in diminishing HEWL amyloid fibril formation delaying both the nucleation and elongation phases. Disaggregation of previously formed HEWL amyloid fibrils was also enhanced by indole 3-acetic acid. Various medium conditions such

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