Selective thiazoline peptide cyclisation compatible with mRNA display and efficient synthesis

Abstract

Peptide display technologies are a powerful method for discovery of new bioactive sequences, but linear sequences are often very unstable in a biological setting. Macrocyclisation of such peptides is beneficial...

Chemo-ribosomal synthesis of atropisomeric and macrocyclic peptides with embedded quinolines

“…To assess whether atropisomeric quinolines could be introduced within ribosomal peptides, we first confirmed that Friedländer reaction of peptide 28 with (2-aminophenyl)(o-tolyl)methanone (26) in AcOH at 60 °C for 48 h produced the expected product 29 as a roughly 41:59 mixture of atropisomeric products, as determined by 1 H NMR (Fig. 4a).…”

“…Indeed, Lewis acids such as the chloride salts of Ce(III) 70 and Fe(III) 71 as well as the triflate salts of Yb(III) 72 , Y(III) 73 , and Zn(II) 74 , can promote Friedländer reactions of β-ketoesters 48 . To evaluate if they could improve atropisomer-forming reactions of β-keto amide 2-P1, we screened their effect (at 20 mol%) on the Friedländer reaction of dipeptide 5 and (2-aminophenyl)(o-tolyl)methanone (26) to generate the quinoline 27 (Supplementary Fig. 9 and Supplementary Table 3).…”

“…Although widely employed, each of these methods suffers from at least one liability with respect to downstream applications and none provide added value: Disulfide bonds are reversible, while thioethers are flexible and, like click reaction products, prone to oxidation. Alternative macrocyclization strategies that generate stable and drug-like linkers are widely recognized as an unmet need 9,[22][23][24][25][26][27] . Chemistry that exploits the macrocyclization event to establish a known pharmacophore within the peptide backbone prior to biological display is a promising strategy towards this end 28 .…”

Engineering tRNAs for the Ribosomal Translation of Non-proteinogenic Monomers

“…Similar to in vivo genetic code expansion, the FIT system is able to easily translate side chain-functionalized l -AA derivatives. Generally, tRNA AsnE2 is used, as EF-Tu affinity is not an issue, though for some bulkier npMs the optimized T stem of tRNA GluE2 may be necessary (refs , , , , , , , , , and − ). In a similar manner to RaPID, the PURE system has also been combined with Mj TyrRS/tRNA opt CUA pairs for mRNA display selections by Iskandar and co-workers in 2023. , As the cotranslational incorporation of l -AA derivatives is more efficient than backbone-modifying npMs and has been extensively reviewed elsewhere, it will not be discussed in detail. ,, However, these npMs are nevertheless important and are often used in RaPID selections for their beneficial side chains.…”

Biocompatible strategies for peptide macrocyclisation

“…Jongkees, Nitsche & co-workers recently reported a similar strategy where they combined the selective reactivity of N-terminal cysteine and non-N-terminal cysteine to construct bicyclic peptide libraries. 211 …”