Disparate Effect of Hybrid Peptidomimetics Containing Isomers of Aminobenzoic Acid on hIAPP Aggregation.

Abstract

The abnormal misfolding of human islet amyloid polypeptide (hIAPP) in pancreatic β-cells is implicated in the progression of type II diabetes (T2D). With the prevalence of T2D increasing worldwide, preventing the aggregation of hIAPP has been recognized as a promising therapeutic strategy to control this disease. Recently, a class of novel conformationally restricted β-sheet breaker hybrid peptidomimetics (BSBHps) was found to demonstrate efficient inhibitory ability toward amyloid formation of hIAPP. One (Ile26) or more (Gly24 and Ile26) residues in these six-membered peptide sequences, which have been extracted from the amyloidogenic core of hIAPP, N22FGAIL27, are substituted by three different isomers of the conformationally restricted aromatic amino acid, i.e., aminobenzoic acid (β, γ, and δ), to generate these BSBHps. The presence of the nonproteinogenic aminobenzoic acid moiety renders the BSBHps to be more stable toward proteolytic degradation. The different isomeric BSBHps exhibit contrasting influence on the self-assembly of hIAPP. The BSBHps containing β- and γ-aminobenzoic acid can sufficiently prevent hIAPP aggregation, but those with the δ-aminobenzoic group stabilize the β-sheet-rich aggregate of hIAPP. The difference in the angle between the amino and carboxyl groups in the isomers of the aminobenzoic moiety causes the BSBHps to attain discrete conformation and hence leads to variation in their binding preference with hIAPP and ultimately their inhibitory potency. This guides the pathway for the dissimilar effect of BSBHps on peptide aggregation and, therefore, provides insights into the design considerations for novel drugs against T2D.