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Open AccessArticle

Insulin Hot-Spot Analogs Formed with N-Methylated Amino Acid Residues Inhibit Aggregation of Native Hormone

1
Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland
2
Institute of General Food Chemistry, Faculty of Biotechnology & Food Sciences, Lodz University of Technology, Stefanowskiego 4/10, 90-924 Lodz, Poland
*
Author to whom correspondence should be addressed.
Molecules 2019, 24(20), 3706; https://doi.org/10.3390/molecules24203706
Received: 14 September 2019 / Revised: 7 October 2019 / Accepted: 11 October 2019 / Published: 15 October 2019
(This article belongs to the Section Bioorganic Chemistry)
In this study, N-methylated analogs of hot-spots of insulin were designed and synthesized, in the expectation that they would inhibit the aggregation of both insulin hot-spots and the entire hormone. Synthesis of insulin “amyloidogenic” analogs containing N-methylated amino acid residues was performed by microwave-assisted solid phase according to the Fmoc/tert-Bu strategy. As a coupling reagent 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium toluene-4-sulfonate (DMT/NMM/TosO-) was used. Three independent methods were applied in aggregation studies of the complexes of insulin with its N-methylated peptides. Additionally, circular dichroism (CD) measurements were used to confirm that aggregation processes did not occur in the presence of the N-methylated analogs of hot-spot insulin fragments, and that insulin retains its native conformation. Of the seven N-methylated analogs of the A- and B-chain hot-spots of insulin, six inhibited insulin aggregation (peptides 1 and 37). All tested peptides were found to have a lower ability to inhibit the aggregation of insulin hot-spots compared to the capability to inhibit native hormone aggregation. View Full-Text
Keywords: inhibition of insulin aggregation; aggregation; N-methylated analogs of insulin hot-spots; microwave-assisted solid-phase peptide synthesis; triazine coupling reagent inhibition of insulin aggregation; aggregation; N-methylated analogs of insulin hot-spots; microwave-assisted solid-phase peptide synthesis; triazine coupling reagent
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Swiontek, M.; Wasko, J.; Fraczyk, J.; Galecki, K.; Kaminski, Z.J.; Kolesinska, B. Insulin Hot-Spot Analogs Formed with N-Methylated Amino Acid Residues Inhibit Aggregation of Native Hormone. Molecules 2019, 24, 3706.

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