Functionalised staple linkages for modulating the cellular activity of stapled peptides

Abstract

A divergent synthetic strategy for generating helical p53 peptides bearing functionalised staple linkages, allowing for efficient optimisation of cellular activity.

Stapled peptide design: principles and roles of computation

“…Double-click reactions involving two side chains with azido functional groups at the i, i + 4 or i + 7 positions and a dialkynyl linker (Fig. 1c) have also been used to enhance helicity in peptides derived from the GCN4 leucine zipper and p53 transactivation domain [51,52]. These reactions allow for wider exploration of chemical space than hydrocarbon staples because different dialkynyl linkers can be installed.…”

“…Limited investigations into the effect of stereochemistry indicate that the (S,R) configuration might be more favourable than (S,S) for the i, i + 4 triazole staple [63], although a more exhaustive study is required to examine and characterise all possible stereochemical combinations. Only the (S,S) configuration has been adopted for the i, i + 7 triazole staple in double-click stapling and the effect of stereochemistry has not been examined [52]. So far, the unnatural residues used to form the triazole staples are monosubstituted, and do not have an a-methyl group.…”

Peptide stapling techniques based on different macrocyclisation chemistries

“…36,37 The aim of our investigations was to exploit the two-component nature of the double-click reaction by stapling a single peptide with different functionalised dialkynyl linkers (Fig. 13).…”

Macrocyclic α-Helical Peptide Drug Discovery

“…Another example includes the design of p53 and structurally related phage display-derived stapled helical peptides having high binding affinity to both MDM2 and MDMX that has been successfully achieved. 42,57,58,65,66,72,79,81,82,87,94,95 In the case of BID BH3 stapled peptides, proof-of-concept studies demonstrating in vivo efficacy in a human leukemia xenograft model (10 mg kg À1 dosing intravenously qd for seven days) were achieved, subsequent to an iterative process to identify a molecule having enhanced proteolytic and serum stability, high binding affinity to anti-apoptotic protein Bcl-2, cell penetration and mitochondrial co-localization, and cytochrome C-driven cellular apoptosis. 43 Recent studies have further shown the successful development of BIM BH3 and BID BH3 stapled peptides which are capable of directly activating the pro-apoptotic protein BAX to affect apoptosis.…”

“…[19][20][21][22][23][24][27][28][29] and 62 for reviews) for the modulation a plethora of intracellular targets (i.e. Bcl2-family, 19,[22][23][24]43,47,48,58,[67][68][69][70][71]76,77,83,92,93,98 p53:MDM2/X, 42,57,65,66,72,79,81,82,87,89,94,95 MAML:Notch, 49 eIF4E, 158 ERa/ERb, 50 IRS1, 84 HIF-1:p300, 56,90 RAS:SOS, 59 Rab-GTPase, 96 b-catenin, 64,78,80 protein kinase-A, 91 RPA, 97 HIV-1 integrase, …”