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, N 22 FGAIL 27 , 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 βand 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.

Pathways of hLL-3717-29 Aggregation Give Insight into the Mechanism of α-Amyloid Formation

“…The final matrix was normalized and depicted as a heat map using the Seaborn library of Python. For Phe rings having center-of-mass (COM) distances within 6.5 Å, three different stacking interactions are possible based on their relative orientation: (1) 0–30/150–180° for parallel­(Par) stacking, (2) 30–60/120–150° for herringbone (Herr) interactions, and (3) 60–120° (Perp) for perpendicular stacking Figure S1 in the Supporting Information summarizes the geometric definition of π-stacking interactions.…”

“…For Phe rings having center-of-mass (COM) distances within 6. stacking. 81 Figure S1 in the Supporting Information summarizes the geometric definition of π-stacking interactions. The effect of mutations on the binding energy of the peptides was studied using the Alanine scanning technique implemented in the MMGBSA method of AMBER18.…”

Elucidating the Hydrotropic Mechanism of the Antagonistic Salt PPh4Cl

“…To better understand the dissimilarity in the interaction between molecules, we calculated the preferential interaction parameters τ TP DR and τ DR TP (Figure 6). 76 τ B A , which signifies the interaction of A−A over A−B, is positive when A− A interactions are favored over A−B interactions. We obtain positive values for τ TP DR , which suggests favorable interactions among DR molecules compared to DR−TP interaction.…”

Exploring the Curvature-Dependence of Boron Nitride Nanoparticles on the Inhibition of hIAPP Aggregation

“…In this regard, a variety of inhibitors have been identified as potential drug candidates to treat T2D. These include natural compounds, small molecules and peptides, peptidomimetics, and nanomaterials. − Recently, due to the ease of blood–brain barrier penetration, application of surface-functionalized ligands, and body clearance, utilization of nanoparticles in anti-aggregation research has received great attention. ,, The nanoparticles have a large surface-to-volume ratio, which enables them to provide strong adsorption sites to trap amyloid peptides, both in vitro and in vivo, thus controlling self-aggregation possibility . The efficiency of these inhibitors depends on the shape, size, surface charge and ligands, and lattice facets of the nanoparticles. , …”