INHIBITING TRANSTHYRETIN CONFORMATIONAL-CHANGES THAT LEAD TO AMYLOID FIBRIL FORMATION

Insoluble protein fibrils resulting from the self-assembly of a confor mational intermediate are implicated as the causative agent in several severe human amyloid diseases, including Alzheimer's disease, familia l amyloid polyneuropathy, and senile systemic amyloidosis, The latter two diseases are associated,vith transthyretin (TTR) amyloid fibrils, which appear to form in the acidic partial denaturing environment of t he lysosome, Here we demonstrate that flufenamic acid (Flu) inhibits t he conformational changes of TTR associated with amyloid fibril format ion. The crystal structure of TTR complexed with Flu demonstrates that Flu mediates intersubunit hydrophobic interactions and intersubunit h ydrogen bonds that stabilize the normal tetrameric fold of TTR, A smal l-molecule inhibitor that stabilizes the normal conformation of a prot ein is desirable as a possible approach to treat amyloid diseases. Mol ecules such as Flu also provide the means to rigorously test the amylo id hypothesis, i.e., the apparent causative role of amyloid fibrils in amyloid disease.