Disaggregation of Amylin Aggregate by Novel Conformationally Restricted Aminobenzoic Acid containing alpha/beta and alpha/gamma Hybrid Peptidomimetics

作者：Paul Ashim; Kalita Sourav; Kalita Sujan; Sukumar Piruthivi; Mandal Bhubaneswar

来源：Scientific Reports, 2017, 7(1): 40095.

DOI：10.1038/srep40095

Diabetes has emerged as a threat to the current world. More than ninety five per cent of all the diabetic population has type 2 diabetes mellitus (T2DM). Aggregates of Amylin hormone, which is co-secreted with insulin from the pancreatic beta-cells, inhibit the activities of insulin and glucagon and cause T2DM. Importance of the conformationally restricted peptides for drug design against T2DM has been invigorated by recent FDA approval of Symlin, which is a large conformationally restricted peptide. However, Symlin still has some issues including solubility, oral bioavailability and cost of preparation. Herein, we introduced a novel strategy for conformationally restricted peptide design adopting a minimalistic approach for cost reduction. We have demonstrated efficient inhibition of amyloid formation of Amylin and its disruption by a novel class of conformationally restricted beta-sheet breaker hybrid peptidomimetics (BSBHps). We have inserted beta,gamma and delta -aminobenzoic acid separately into an amyloidogenic peptide sequence, synthesized alpha/beta, alpha/gamma and alpha/delta hybrid peptidomimetics, respectively. Interestingly, we observed the aggregation inhibitory efficacy of alpha/beta and alpha/gamma BSBHps, but not of alpha/delta analogues. They also disrupt existing amyloids into non-toxic forms. Results may be useful for newer drug design against T2DM as well as other amyloidoses and understanding amyloidogenesis.

• 出版日期2017-1-5