Solid-phase peptide synthesis on disulfide-linker resin followed by reductive release affords pure thiol-functionalized peptides

Abstract

Thiol groups are suitable handles for site-selectively modifying, immobilizing or cyclizing individual peptides or entire peptide libraries. A limiting step in producing the thiol-functionalized peptides is the chromatographic purification, which...

Thioether analogues of the pituitary neuropeptide oxytocin via thiol–ene macrocyclisation of unprotected peptides

“…Synthesis of further disulfide peptide analogues is under investigation and is to lead to more stable analogues. Further, we envisage that this approach using simple thioether linkages would be amenable to synthesis of peptide libraries, in particular using peptides of high crude purity produced using thiol resins, 25 work that is currently under investigation.…”

Cyclic Peptides for Drug Development

“…At first glance, this approach is limited by the rather small libraries that can be screened, though recent technology developments have enabled the generation and screening of libraries comprising ten-thousands of different cyclic peptides. For example, automated and high-throughput synthesis techniques can provide thousands of mostly pure peptides, [69] and novel methods allow for the combinatorial cyclization and diversification of libraries by coupling chemical fragments at a nanomole scale using contact-less acoustic dispensing. [70] Screening such libraries has produced ligands to several model targets, such as proteases, as well as more difficult targets, including protein-protein interactions.…”

Nanomole‐scale photochemical thiol‐ene chemistry for high‐throughput late‐stage diversification of peptide macrocycles

“…Linear dithiol peptides were synthesised as previously reported. [ 10 ] Briefly, peptides were prepared via Fmoc‐based solid‐phase peptide synthesis (SPPS) on disulphide resin. Amino acid couplings were performed using HBTU and i‐ Pr 2 NEt for 1 h and deprotections were carried out with 20% piperidine in DMF (2 × 5 min).…”

“…Recently, the Heinis laboratory has developed efficient procedures for synthesis of peptidic macrocycles via synthesis on disulphide resins, facilitating cyclative release to afford disulphide macrocycles [ 9 ] or reductive release followed by cyclization with bis‐electrophilic reagents to yield dithioether macrocycles (Figure 1a). [ 10 ]…”

“…or reductive release followed by cyclization with bis-electrophilic reagents to yield dithioether macrocycles (Figure 1a). [10] Previously, the use of solution-phase acylation of macrocycles containing diamino acids for diversification in high-throughput has been reported, enabling the synthesis of targeted libraries of small peptidic macrocycles to furnish binders against challenging targets. [4] However, this approach is limited in scope regarding other two-electron reactive groups such as amines and carboxylic acids that are found in peptides.…”