Intervention of hIAPP amyloid aggregation by smart posttransmuting anti-amyloidogenic peptidomimetics

Abstract

hIAPP, human islet amyloid polypeptide, aggregates have been implicated in the development of type 2 diabetes mellitus (T2DM). As a prelude to developing a potential cure for T2DM, researchers worldwide have employed various strategic molecular entities to target β-sheet-rich hIAPP aggregates, known as disruptors, or to prevent the self-assembly of hIAPP, known as inhibitors. Peptide-based strategies are at the forefront. Most β-sheet breakers have a pre-installed breaker element, notably Proline. Here, we describe a different approach that works in a pro-drug fashion-the use of the infamous aspartimide formation. The designed smart peptides sneak into the aggregating system as standard peptides and undergo various aspartimide-induced chemical transformations, developing into an anti-amyloidogenic agent. The peptide develops a pre-programmed kink via aspartimide formation. The kink misaligns the β-sheet topology of the hIAPP aggregates, significantly disrupting them. The reaction cascade is followed by racemization and nucleophilic ring opening by water, resulting in the formation of L-α/β and D-α/β aspartyl peptides. The L-peptides and D-isopeptides are antiamyloidogenic. Moreover, the negative charges on such peptidomimetics improve solubility and recognisability. The strategy could be a promising leap toward developing therapeutics for amyloidogenic type 2 diabetes mellitus (T2DM). This study will also help to understand the aggregation-disaggregation mechanism of hIAPP.2