This study examined how stapling of a peptide drug can improve its stability.
Circular dichroism data showed that the wildtype peptide (HIF-1α) as well as its constrained derivatives adopted a conformation dominated by random coil in absence of the binding partner (p300).
However, the structure of the stapled peptide showed increased helicity in the bound state, as reflected by the difference between the spectrum of a mix containing peptide and p300 and an additive spectrum of the individual compounds.
A comparison with the difference spectra for wildtype and the oxidised form of the constrained peptide reveals that the increase in helicity for the bound state was highest for the stapled peptide.
Unexpectedly, increased inhibition potency did not correlate with pre-organisation of the α-helical conformation in the unbound state, but rather with stabilisation of the bioactive conformation of the bound state.
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