Straightforward strategy to substitute amide bonds by 1,2,3‐triazoles in peptaibols analogs using Aibψ[Tz]‐Xaa dipeptides

Abstract

Structured peptides gained more attention over a decade because of their biological properties, biocompatibility and ability to act as modulators of protein/protein interactions, antibiotics, analgesics, immunosuppressants or as imaging agents to cite a few relevant applications. However, their poor bioavalability due in part to the susceptibility of the peptide bond to proteolytic cleavages often impaired their development and considerably limited their therapeutic use. To circumvent these problems, many efforts are undertaken to discover stable amide bond mimics resistant to proteolytic degradation. Among them the 1,2,3-triazole emerged as a highly stable analogue of the trans-peptide bond to generate bioactive peptides. Here we report a convenient approach to readily substitute amide bonds by triazole rings in Aib-containing peptides using Aibψ[Tz]-Xaa dipeptide-like units. We defined their application in solid phase synthesis and generated short model peptide sequences to study the impact of the triazole incorporation on their conformations in solution by circular dichroism and nuclear magnetic resonance spectroscopies.

1,4-Disubstituted 1H-1,2,3-Triazole Containing Peptidotriazolamers: A New Class of Peptidomimetics With Interesting Foldamer Properties

“…Eventually it has been shown, that a carbodiimide-mediated preactivation in DCM, without the use of a base, and subsequent coupling with the use of 2,4,6-collidine, effectively prevents epimerization during the coupling of the free acid of the triazole-building block 4 (Kracker et al, 2018). K Ben Haj Salah et al also used the building block approach for their synthesis of peptaibols analogs containing AibΨ[4Tz]-Xaa dipeptides (Ben Haj Salah et al, 2015).…”

Enhancing the Antimicrobial Activity of Alamethicin F50/5 by Incorporating N‐terminal Hydrophobic Triazole Substituents.

“…The Alm derivatives containing a modified N‐terminus were prepared using published synthetic protocols . Briefly, peptides were assembled by stepwise synthesis using 9‐fluorenylmethoxycarbonyl (Fmoc)/ t Bu strategy on a chlorotrityl resin preloaded with phenylalaninol at a 0.1 mmol scale.…”

Isolation and Synthesis of Laxaphycin B-Type Peptides: A Case Study and Clues to Their Biosynthesis

“…Due to its numerous advantages including the avoidance of repetitive purification steps and flexibility, SPPS was used preferentially to the in-solution strategy. Furthermore, we make use of an instrumentation combining the advantages of automation and microwave heating that speeds up synthesis and increases overall yield and purity for difficult peptide sequences [ 17 , 18 , 19 , 20 ].…”