LAUSR

To develop anti-amyloidogenic inhibitors for ameliorating the treatment of diabetes, herein, we have synthesised amphiphilic block copolymers with side-chain fatty acid (FA) moieties via reversible addition fragmentation chain-transfer (RAFT) polymerization. We addressed the unexplored role of FA pendants in the FA-tethered block copolymers (FABC) towards modulating the insulin fibrillation process with the aid of different biophysical techniques. Experimental findings established that FABC micelles can elongate the lag phase time to a greater extent and exhibit significant inhibitory potencies, with the more pronounced effect observed in stearic acid-based polymeric micelles (SABC475). Furthermore, conformational modulation using circular dichroism spectroscopic measurements demonstrates their potential role as effective inhibitors of insulin fibrils through reducing the β-sheet contents. Interestingly, the FABC micelles can also disintegrate the matured fibrils and effectively diminish the fibril induced toxicity. Hydrophobic interaction and hydrogen (H) bonding are the two major driving forces that are equally responsible for the almost complete prevention of insulin aggregated species. Theoretical simulation results further support our experimental observations in explaining the inhibitory rate of the insulin fibrillation process in the presence of different FABC micelles. Overall, we envision that the reported study will provide a novel path to develop a new class of anti-amyloid polymeric inhibitors.