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Studies on acid stability and solid-phase block synthesis of peptide–peptoid hybrids: ligands for formyl peptide receptors

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Abstract

α-Peptoids as well as peptide/α-peptoid hybrids and peptide/β-peptoid hybrids constitute major classes of proteolytically stable peptidomimetics that have been extensively investigated as mimetics of biologically active peptides. Representatives of lipidated peptide/β-peptoid hybrids have been identified as promising immunomodulatory lead compounds, and hence access to these via protocols suitable for gram-scale synthesis is warranted to enable animal in vivo studies. Recent observations indicated that several byproducts appear in crude mixtures of relatively short benzyl-based peptide/β-peptoid oligomers, and that these were most predominant when the β-peptoid units displayed an α-chiral benzyl side chain. This prompted an investigation of their stability under acidic conditions. Simultaneous deprotection and cleavage of peptidomimetics containing either α-chiral α- or β-peptoid residues required treatment with strong acid only for a short time to minimize the formation of partially debenzylated byproducts. The initial work on peptide/β-peptoid oligomers with an alternating design established that it was beneficial to form the amide bond between the carboxyl group of the α-amino acid and the congested amino functionality of the β-peptoid residue in solution. To further simplify oligomer assembly on solid phase, we now present a protocol for purification-free solid-phase synthesis of tetrameric building blocks. Next, syntheses of peptidomimetic ligands via manual solid-phase methodologies involving tetrameric building blocks were found to give more readily purified products as compared to those obtained with dimeric building blocks. Moreover, the tetrameric building blocks could be utilized in automated synthesis with microwave-assisted heating, albeit the purity of the crude products was not increased.

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Acknowledgements

We acknowledge Birgitte Simonsen for the purification of peptidomimetics. NMR equipment used in this work was purchased via Grant No. 10-085264 from The Danish Research Council for Independent Research|Nature and Universe.

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Correspondence to Henrik Franzyk.

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Handling Editor: F. Albericio.

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Hansen, A.M., Skovbakke, S.L., Christensen, S.B. et al. Studies on acid stability and solid-phase block synthesis of peptide–peptoid hybrids: ligands for formyl peptide receptors. Amino Acids 51, 205–218 (2019) doi:10.1007/s00726-018-2656-x

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Keywords

  • Peptidomimetics
  • Peptoids
  • Solid-phase synthesis
  • Acid stability
  • Formyl peptide receptor ligands