[30] Design and testing of inhibitors of fibril formation

Amyloid β-peptide (Aβ) is an approximately 40-residue proteolytic fragment of amyloid precursor protein (APP). Genetic, neuropathologic, and transgenic modeling studies implicate the expression and accumulation of Aβ as a necessary but not necessarily, by itself, sufficient step in the pathogenesis of AD. While larger peptides (various analogs of Aβ, modified forms of Aβ, and other proteins such as apolipoprotein E, α2-macroglobulin, and transthyretin) can have inhibitory effects on fibrillogenesis, such materials are less appealing as leads for drug development than much smaller molecules. The strong binding of dyes such as Congo red and thioflavin T to amyloid and the inhibition by 4'-deoxy-4-iododoxorubicin (IDOX) of prion protein amyloid formation, Immunoglobulin G (IgG) light chain amyloidosis, and insulin fibrillogenesis suggest the possibility of preparing therapeutics based on these compounds. However, IDOX has acute cytotoxicity that precludes its use in chronic therapy. More recently, several groups, including ours, have begun to work with small fragments of the Aβ sequence, which have been reported to inhibit Aβ polymerization. This chapter describes elements of how it has approached the design and testing of such compounds.