A Thiolactone Strategy for Straightforward Synthesis of Disulfide‐Linked Side‐Chain‐to‐Tail Cyclic Peptides Featuring an N‐Terminal Modification Handle

Abstract

The development of straightforward and versatile peptide cyclisation methods is highly desired to meet the demand for more stable peptide-based drugs. Herein, a new method for the synthesis of side-chain-to-tail cyclic peptides with the simultaneous introduction of an N-terminal handle, based on the introduction of an N-terminal thiolactone building block, is described. A primary amine liberates a homocysteine analogue from the thiolactone building block, which further enables cyclisation of the peptide through disulfide-bond formation with a C-terminal cysteamine. Postcyclisation modification can be achieved by using small bifunctional amines. Alternatively, the synthesis of lipopeptides is demonstrated through direct thiolactone opening with long-chain alkyl amines.

Direct comparison of solution and solid phase synthesis of sequence-defined macromolecules

“…As it was already demonstrated previously by our group that a large variety of side chains can be introduced to the oligomeric backbone by varying the aldehyde component in the P-3CR, this study was limited to three different aldehydes to generate " [ABC] x "-sequences. 29,30,34,35 Using L1 and L2, a two-step, iterative cycle was developed, consisting of a TAD-based Diels-Alder reaction, followed by the P-3CR (Scheme 1). Both reactions reached quantitative conversions and yields and were carried out both on the solid phase and in solution.…”

“…6,24 A common route towards sequence-defined oligomers, offering full control over each monomer unit, is the iterative synthesis approach. 7,[25][26][27][28][29][30][31][32] This step-by-step growth of the macromolecule is necessary to ensure a perfectly defined sequence as well as monodispersity. Whilst many different approaches exist, the use of multi-component reactions seems to be a logical choice within this area and such reactions have indeed been shown to be highly effective tools for the synthesis of sequence-defined macromolecules.…”

Enhancing activity of food protein‐derived peptides: An overview of pretreatment, preparation, and modification methods

“…Cyclization is a type of peptide modification that involves forming a covalent bond between the N‐ and C‐termini of a peptide, resulting in a cyclic structure. Cyclic peptides have gained significant attention in biomedicine due to their unique properties and diverse applications (Van Lysebetten et al., 2018). One key advantage of cyclic peptides is their enhanced stability compared to linear peptides (Wang & Craik, 2018).…”

Methodologies for Backbone Macrocyclic Peptide Synthesis Compatible With Screening Technologies

“…With SPPS and further chemical modifications, various side-chain-involved cyclization tactics through lactam bridges (Taylor, 2002), disulfide bonds (Postma and Albericio, 2014), and thiolactone linkage (Van Lysebetten et al, 2018) have been reported in the past two decades. In contrast, SPPS of amide bond-joined backbone macrocyclic peptides proved to be difficult due to the limitation of acyl-derivatives that can react with the solid phase and C-terminal residue.…”