Bioorthogonal Peptide Macrocyclization Using Oxime Ligation

Abstract

The biocompatible synthesis of constrained peptides is challenging. Oxime ligation is a bioorthogonal technique frequently used for protein bioconjugation. We report a straightforward method to install N-terminal ketones and aminooxy side chains during standard solid-phase peptide synthesis. Cyclization occurs spontaneously after acidic cleavage or in aqueous buffer. We demonstrate the facile synthesis of protease inhibitors with varying conformational constraint. The most constrained peptide displayed an activity 2 orders of magnitude higher than its linear analog.

Biocompatible strategies for peptide macrocyclisation

“…216–218 We have demonstrated a peptide cyclisation strategy utilising intramolecular oxime ligation between an alkoxyamine amino acid and an N-terminal α-ketoamide (Scheme 9A). 219…”

Peptide macrocyclisation via intramolecular interception of visible-light-mediated desulfurisation

“…, ‘Click Chemistry’), Staudinger ligation 32 and azide-phosphonite chemistry. 33 Simple imine 34 and oxime 35 bond formation has been utilized, as well as more complex transition metal (TM)-catalysed 36–41 and multi-component chemistry. 42 Radical reactions such as thiol–ene 43–45 and, more recently, decarboxylative photoredox catalysis 46 and C–H alkylation 47 have also been successfully applied.…”

Proximity-Induced Ligation and One-Pot Macrocyclization of 1,4-Diketone-Tagged Peptides Derived from 2,5-Disubstituted Furans upon Release from the Solid Support

“…In recent years, efforts were increasingly devoted to the realization of one-pot macrocyclization chemistries that rely on simple reaction conditions and the realization of reagent-less approaches. Among these cyclizations, we can find α-ketoacid-hydroxylamine (KAHA) ligations, 17 acid-catalyzed transamidation of N-terminal maleimides, 18 Diels–Alder reaction of maleimides on dienes and furans, 19 cysteine SNAr reaction on thioethers, 20 CyClick reactions exploiting the intramolecular quenching of an imine intermediate, 21 or the reversible imminoborane 22 and oxime 23 reactions.…”