Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924, Lodz, Poland.
Institute of General Food Chemistry, Faculty of Biotechnology & Food Sciences, Lodz University of Technology, Stefanowskiego 4/10, 90-924, Lodz, Poland.
Chem Biodivers. 2021 Jan;18(1):e2000842. doi: 10.1002/cbdv.202000842. Epub 2020 Dec 17.
Amylin (hIAPP) aggregation leads to the formation of insoluble deposits and is one of the factors in the development of type II diabetes. The aim of this research was to find N-methylated analogs of the aggregating amylin fragments 18-22, 23-27, and 33-37, which would not themselves be susceptible to aggregation and would inhibit the aggregation of the amyloidogenic cores of the hormone. None of the analogs of fragment 18-22 containing one or two N-methylated amino acid residues showed any tendency to aggregate. Only the peptide H-F(N-Me)GA(N-Me) IL-OH (6) derived from the 23-27 hIAPP hot spot did not form fibrous structures. All analogs of the 33-37 amylin fragment were characterized by the ability to form aggregates, despite the presence of N-methylated amino acids in their structures. N-Methylated peptides 1-5 demonstrated inhibitory properties against the aggregation of fragment 18-22. Aggregation of the amyloidogenic core of 23-27 was significantly inhibited by N-methylated peptides 1-3 derived from the (18-22) H-HSSNN-OH fragment and by the H-F(N-Me)GA(N-Me)IL-OH (6) fragment derived from the 23-27 amylin hot spot. Fragment (33-37) H-GSNTY-NH was found to be inhibited in the presence of N-methylated peptides 1-3 derived from the 18-22 fragment and by the double methylated peptide H-F(N-Me)GA(N-Me)IL-OH (6). Research on the possibility of using N-methylated analogs of amyloidogenic amylin cores as inhibitors of hormone aggregation is ongoing, with a focus on finding the minimum concentration of N-methylated peptides capable of inhibiting the aggregation of hIAPP hot spots.
胰岛淀粉样多肽（hIAPP）的聚集导致不溶性沉积物的形成，是 II 型糖尿病发展的因素之一。本研究的目的是寻找可聚集的胰岛淀粉样多肽片段 18-22、23-27 和 33-37 的 N-甲基化类似物，这些类似物本身不易聚集，并能抑制激素淀粉样核心的聚集。含有一个或两个 N-甲基化氨基酸残基的片段 18-22 的类似物都没有显示出任何聚集的趋势。只有来自 23-27 hIAPP 热点的肽 H-F（N-Me）GA（N-Me）IL-OH（6）没有形成纤维结构。尽管其结构中存在 N-甲基化氨基酸，但所有 33-37 淀粉样多肽片段的类似物都表现出形成聚集物的能力。N-甲基化肽 1-5 对 18-22 片段的聚集具有抑制作用。N-甲基化肽 1-3 来源于（18-22）H-HSSNN-OH 片段和来源于 23-27 淀粉样多肽热点的 H-F（N-Me）GA（N-Me）IL-OH（6）片段显著抑制了 23-27 淀粉样核心的聚集。在存在来源于 18-22 片段的 N-甲基化肽 1-3 和双甲基化肽 H-F（N-Me）GA（N-Me）IL-OH（6）的情况下，发现片段（33-37）H-GSNTY-NH 受到抑制。目前正在研究将淀粉样核心的 N-甲基化类似物作为激素聚集抑制剂的可能性，重点是寻找能够抑制 hIAPP 热点聚集的最小浓度的 N-甲基化肽。
