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. 2023 Oct 13;29(57):e202301949.
doi: 10.1002/chem.202301949. Epub 2023 Sep 8.

Peptide Macrocyclization Guided by Reversible Covalent Templating

Josef M Maier  1 , Stephanie A Valenzuela  1 , Aevi van der Stok  1 , Arjun K Menta  1 , Yuka Shimizu  1 , Phuoc H Ngo  1 , Andrew D Ellington  1   2 , Eric V Anslyn  1
Affiliations

Peptide Macrocyclization Guided by Reversible Covalent Templating

Josef M Maier et al. Chemistry. .

Abstract

The creation of complementary products via templating is a hallmark feature of nucleic acid replication. Outside of nucleic acid-like molecules, the templated synthesis of a hetero-complementary copy is still rare. Herein we describe one cycle of templated synthesis that creates homomeric macrocyclic peptides guided by linear instructing strands. This strategy utilizes hydrazone formation to pre-organize peptide oligomeric monomers along the template on a solid support resin, and microwave-assisted peptide synthesis to couple monomers and cyclize the strands. With a flexible templating strand, we can alter the size of the complementary macrocycle products by increasing the length and number of the binding peptide oligomers, showing the potential to precisely tune the size of macrocyclic products. For the smaller macrocyclic peptides, the products can be released via hydrolysis and characterized by ESI-MS.

Keywords: dynamic covalent bonds; peptides; replication; sequence defined; templating.

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Figures

Figure 1.
Figure 1.
(A) Synthesis of template 1 with aldehyde monomers using solid phase peptide synthesis and click chemistry and (B) the complementary hydrazide peptide oligomers 2, 2a, 2b, and 2c with amino acid sequences shown. All amino acids used in peptide synthesis are L-amino acids.
Figure 2.
Figure 2.
(top) Template, cycle, and release strategy to create peptide macrocycle cHH, 5. (bottom) Extracted ion chromatograms of the template, 1 (AA), the loaded template, 3 (AA:H:H), and the template-macrocycle complex, 4 (AA:cHH).
Figure 3.
Figure 3.
Extracted ion chromatograms of template macrocycle complexes (AA:cHH) made from peptide (a) monomer, (b) trimers, and (c) tetramers and structures of the corresponding macrocycles of 2, 6, and 8 amino acids in size.
Figure 4.
Figure 4.
(top) LC (290 nm) chromatogram of the hydrolysis of crude 4c(AA:cHH) resulting in the partial release of the instructing template and macrocycle product, with overlayed EICs of each component show below. (bottom) LC (280 nm) and EIC chromatograms of the full release of the macrocyclic product and reduced template using TIS.
Figure 5.
Figure 5.
(A) Template strand 6 containing four aldehydes. (B) Extracted ion chromatograms of the AAAA:cHHHH template macrocycle complex, 8. (C) Structure of the resulting 12 membered macrocycle. (D) Template strand 9 containing three aldehydes. (E) Extracted ion chromatograms of the AAA:cHHH template macrocycle complex, 11. (F) Structure of the resulting 9 membered macrocycle.
See this image and copyright information in PMC

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