gossypetin and Immunoglobulin-Light-chain-Amyloidosis

AL amyloidosis is a life-threatening disease characterized by the deposition of amyloidogenic immunoglobulin light chain secreted from clonal plasma cells. Here we established an in-vitro screening system of amyloid inhibition of a variable domain in λ6 light chain mutant (Vλ6), Wil, and screened a food-additive compound library to identify compounds inhibiting the fibril formation. We found gossypetin and isoquercitrin as novel inhibitors. NMR analysis showed that both compounds directly interacted with natively-folded Wil, and proteolysis experiments demonstrated that these compounds conferred proteolytic resistance, suggesting that the compounds enhance the kinetic stability of Wil. Since gossypetin and isoquercitrin specifically interacted with the protein at micromolar concentrations, these compounds could be used as lead to further develop inhibitors against AL amyloidosis.

Topics: Amyloid; Antioxidants; Catechin; Dose-Response Relationship, Drug; Flavonoids; Humans; Immunoglobulin lambda-Chains; Immunoglobulin Light-chain Amyloidosis; Kinetics; Magnetic Resonance Spectroscopy; Molecular Structure; Mutation; Protein Binding; Protein Stability; Quercetin; Time Factors