Abstract
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 β-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 β-sheet breaker hybrid peptidomimetics (BSBHps). We have inserted β, γ and δ -aminobenzoic acid separately into an amyloidogenic peptide sequence, synthesized α/β, α/γ and α/δ hybrid peptidomimetics, respectively. Interestingly, we observed the aggregation inhibitory efficacy of α/β and α/γ BSBHps, but not of α/δ 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.
Highlights
Function Aggregating/control inhibitor/control inhibitor inhibitor inhibitor inhibitor/control inhibitor inhibitor inhibitor recognition segment is accepted as a promising therapeutic approach against amyloid formation and its disruption
We hypothesized that the hybrid peptides containing β, γand δaminobenzoic acids would be more stable towards proteolytic degradation[27,28], and a better candidate that inhibit/disrupt hIAPP aggregation
The different breaker elements were incorporated in all the breaker peptidomimetics keeping the -N-F- dipeptidyl residue same for mentaining the sequence homology with hIAPP22-23
Summary
Function Aggregating/control inhibitor/control inhibitor inhibitor inhibitor inhibitor/control inhibitor inhibitor inhibitor recognition segment is accepted as a promising therapeutic approach against amyloid formation and its disruption. Since, most of these breaker elements contain α-amino acids; they are proteinogenic, unstable against proteolytic degradation. 2-aminobenzoic acids is structurally rigid and favours the formation of helical or turn conformation while present in a peptide sequence[21,22,23]. It is the precursor for the biosynthesis of tryptophan[24]. We have inserted one or more conformationally restricted aromatic amino acids, β(2-aminobenzoic acid), γ(3-aminobenzoic acid) and δ(4-aminobenzoic acid) separately in the hIAPP22-27 peptide sequence, synthesized α/β, α/γ, and α/δhybrid peptidomimetics, and examined their enzymatic stability and inhibitory effect on the aggregation of the wild type hIAPP1–37. Inherent toxicity of the selected compounds has been checked by MTT reduction assay in human embryonic kidney (HEK) cells in vitro
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