Exploring possibility of promiscuity of amyloid inhibitor: Studies on effect of selected compounds on folding and amyloid formation of proteins

Fibrillar protein aggregates called amyloids are the hallmark of several degenerative diseases. Identification of common drugs which are capable of blocking or inhibiting protein aggregation may be considered as one of the therapeutic approaches directed against amyloid diseases. The present study describes the effect of a few small molecule compounds like clotrimazole, sulconazole and rottlerin towards amyloidogenesis of two model proteins unrelated in terms of structure and sequence such as hen egg white lysozyme and cytochrome c to test promiscuity of amyloid inhibition. Amyloid progression was monitored through Thioflavin T assay and atomic force microscope imaging. Also, the thermodynamic basis of inhibition of fibrillogenesis was analyzed through equilibrium unfolding and unfolding kinetic studies of the proteins in presence of the compounds. Structural alterations in the aggregation-prone intermediate state conformation of the protein in presence of the compounds were monitored through 1-anilino-8-naphthalene sulfonate (ANS) binding studies. Our findings shed some light on the key interactions that guide the path towards protein aggregation and the probable structural and thermodynamic mechanism of inhibition which may provide useful guidelines in development of therapeutics against amyloid diseases. (C) 2011 Elsevier Ltd. All rights reserved.