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. 2024 Apr 28:140:155010.
doi: 10.1016/j.tetlet.2024.155010. Epub 2024 Mar 29.

Squaric esters as peptide stapling reagents

Adam X Wayment  1 , Nye C Johnson  1 , Mariur Rodriguez Moreno  1 , Christopher Stewart  1 , Braxton M Felix  1 , Isaac Lambert  1 , Sarah A Traynor  1 , P Michael Nielson  1 , Grant Q Lofgreen  1 , Shannon L Smith  1 , Madison P Newton  1 , Jordan W Tretbar  1 , Joseph M L Nygaard  1 , Kylie G Harrell  1 , Michael J Kinghorn  1 , David J Michaelis  1
Affiliations

Squaric esters as peptide stapling reagents

Adam X Wayment et al. Tetrahedron Lett. .

Abstract

We report that squaric esters can serve as bifunctional reagents for selective peptide stapling reactions. Formation of the squaric amide staple occurs under mild conditions with amine-containing side chains. We show that short resin-bound peptides are readily stapled on solid phase and that stapling can occur at various relative positions along the peptide and with various amine tether lengths (e.g. Lysine, ornithine, etc). The squaric amide staples are stable to strong acid conditions used to cleave the stapled peptide from the resin and the stapled peptides show an increase in helicity as analyzed through circular dichroism.

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Conflict of interest statement

Conflicts of interest The authors declare that there are no financial conflicts of interest with the present work. Declaration of interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: David J Michaelis reports financial support was provided by National Institutes of Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1.
Figure 1.
Strategies for peptide stapling
Figure 2.
Figure 2.
CD spectra of stapled and unstapled peptide.
See this image and copyright information in PMC

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