A Disulfide Scan of Insulin by [3 + 1] Methodology Exhibits Site-Specific Influence on Bioactivity

Insulin is the principal hormone involved in the regulation of metabolism and has served a seminal role in the treatment of diabetes. Building upon advances in insulin synthetic methodology, we have developed a straightforward route to novel insulins containing a fourth disulfide bond in a [3 + 1] f...

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Veröffentlicht in:ACS chemical biology 2019-08, Vol.14 (8), p.1829-1835
Hauptverfasser: Brunel, Florence M, Mayer, John P, Gelfanov, Vasily M, Zaykov, Alexander N, Finan, Brian, Perez-Tilve, Diego, DiMarchi, Richard D
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container_end_page 1835
container_issue 8
container_start_page 1829
container_title ACS chemical biology
container_volume 14
creator Brunel, Florence M
Mayer, John P
Gelfanov, Vasily M
Zaykov, Alexander N
Finan, Brian
Perez-Tilve, Diego
DiMarchi, Richard D
description Insulin is the principal hormone involved in the regulation of metabolism and has served a seminal role in the treatment of diabetes. Building upon advances in insulin synthetic methodology, we have developed a straightforward route to novel insulins containing a fourth disulfide bond in a [3 + 1] fashion establishing the first disulfide scan of the hormone. All the targeted analogs accommodated the constraint to demonstrate an unexpected conformational flexibility of native insulin. The bioactivity was established for the constrained (4-DS) and unconstrained (3-DS) analogs by in vitro methods, and extended to in vivo study for select peptides. We also identified residue B10 as a preferred anchor to introduce a tether that would regulate insulin bioactivity. We believe that the described [3 + 1] methodology might constitute the preferred approach for performing similar disulfide scanning in peptides that contain multiple disulfides.
doi_str_mv 10.1021/acschembio.9b00420
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subjects Amino Acid Sequence
Disulfides - chemical synthesis
Disulfides - chemistry
Insulin - analogs & derivatives
Insulin - chemical synthesis
Protein Conformation
Protein Engineering - methods
title A Disulfide Scan of Insulin by [3 + 1] Methodology Exhibits Site-Specific Influence on Bioactivity
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