Macrocyclization of Unprotected Peptide Isocyanates

Abstract

A chemistry for the facile two-component macrocyclization of unprotected peptide isocyanates is described. Starting from peptides containing two glutamic acid γ-hydrazide residues, isocyanates can be readily accessed and cyclized with hydrazides of dicarboxylic acids. The choice of a nucleophilic linker allows for the facile modulation of biochemical properties of a macrocyclic peptide. Four cyclic NYAD-1 analogues were synthesized using the described method and displayed a range of biological activities.

Stereoisomerism of stapled peptide inhibitors of the p53-Mdm2 interaction: an assessment of synthetic strategies and activity profiles

“…Cys,1–9 Lys,10–15 Trp,16–18 and Met19). Alternative stabilisation strategies such as alkene,20–25 oxime,26,27 1,2,3-trizole,28–30 hydrazide,31 alkyne,32 spiropyran,33 as well as mixed cross-linkages have also been published 34,35. The resultant macrocycles often possess enhanced proteolytic resistance, specificity and potency, making them ideal pharmacological agents 36–38.…”

Divergent unprotected peptide macrocyclisation by palladium-mediated cysteine arylation

“…The linear control peptide (P1-K ) showed an equilibrium dissociation constant ( K D ) of 5.5 ± 0.6 μM in line with previous literature reports. 27 , 36 All of the mono-aryl linkers with 1,4-substitutions ( P1-B , P1-D , P1-E , and P1-F ) had K D comparable to the linear control. However, variant P1-C with 1,3-substitution showed slightly lower binding affinity ( K D = 21.0 ± 2.4 μM).…”

Recent structural advances in constrained helical peptides

“…The ⍺‐helicity of the constrained peptides was found to be an indicator of the binding affinity of the peptides to C‐CA (C‐terminal domain of HIV‐1 capsid assembly polyprotein), with highly ⍺‐helical peptides having the highest affinity. This approach has contributed to current methods in that it is a two‐component macrocyclization technique that does not depend on the presence of either a cysteine or unnatural amino acid and is simple enough that it can be used to synthesize a diverse library of peptides using easily accessible bifunctional nucleophiles …”