DISCOVERING TRANSTHYRETIN AMYLOID FIBRIL INHIBITORS BY LIMITED SCREENING

Insoluble protein fibrils, resulting from the self-assembly of a confo rmational intermediate are implicated to be the causative agent in sev eral human amyloid diseases including familial amyloid polyneuropathy (FAP) and senile systemic amyloidosis (SSA). These diseases are associ ated with transthyretin (TTR) amyloid fibrils, which appear to form in the acidic partial denaturing environment of a lysosome or endosome. Here we identify several structural classes of small molecules that ar e capable of inhibiting the TTR conformational changes facilitating am yloid fibril formation. A small molecule inhibitor that stabilizes the normal conformation of a protein is desirable as a promising approach to treat amyloid diseases and to rigorously test the amyloid hypothes is, the apparent causative role of amyloid fibrils in amyloid disease. (C) 1998 Elsevier Science Ltd. All rights reserved.