Combination of Kinetically Selected Inhibitors in Trans Leads to Highly Effective Inhibition of Amyloid Formation

Abstract

Amyloid formation plays a role in over 25 human disorders. A range of strategies have been applied to the problem of developing inhibitors of amyloid formation, but unfortunately, many inhibitors are effective only in molar excess and typically either lengthen the time to the onset of amyloid formation, (the lag time), while having modest effects on the total amount of amyloid fibrils produced, or decrease the amount of amyloid without significantly reducing the lag time. We demonstrate a general strategy whereby two moderate inhibitors of amyloid formation can be rationally selected via kinetic assays and combined in trans to yield a highly effective inhibitor which dramatically delays the time to the appearance of amyloid and drastically reduces the total amount of amyloid formed. A key feature is that the selection of the components of the mixture is based on their effect on the time course of amyloid formation rather than on just the amount of amyloid produced. The approach is validated using inhibitors of amyloid formation by islet amyloid polypeptide, the causative agent of amyloid formation in type 2 diabetes and the Alzheimer’s disease Aβ peptide.