Distinct BimBH3 (BimSAHB) Stapled Peptides for Structural and Cellular Studies

Abstract

Hydrocarbon stapling is a chemical approach to restoring and fortifying the natural α-helical structure of peptides that otherwise unfold when taken out of context from the host protein. By iterating the peptide sequence, staple type, and sites of insertion, discrete compositions can be generated to suit a diversity of biochemical, structural, proteomic, cellular, and drug development applications. Here, we reinforce key design considerations to avoid pitfalls and maximize progress when applying stapled peptides in chemistry and biology research.

Helix mimetics: Recent developments

“…In contrast to constrained peptides, which have been tested on a broad range of targets (e.g. a recent review (Bird et al, 2013) highlighted examples of inhibition of~25 distinct PPIs using all-hydrocarbon stapled peptides and this number has grown since), there are far fewer reports on PPI inhibition using helix mimetics. Although it is natural to develop new methodologies on tried and trusted model systems, this should change and several recent studies provide encouragement.…”

Regulation of protein–protein interactions using stapled peptides

“…72 A weaker binding BIM SAHB A (145-164) stapled peptide with moderate helicity compared to the BIM SAHB A (146-166) peptide was used in the in vivo and nuclear magnetic resonance experiments to increase the peptide's solubility and weaken its activation of BAX. BIM SAHB A (146-166) was three residues longer, had higher helicity and higher binding affinity than Bim SAHB A (145-164).…”

Macrocyclic α-Helical Peptide Drug Discovery

“…[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, …”

“…[19][20][21][22][23][24]28, and 29 for reviews). The spectrum of such intracellular a-helical protein-protein interaction target space includes the BH3:Bcl-2 family, 19,[22][23][24]43,47,48,58,[67][68][69][70][71]76,77,83,92,93,98 44,45,88 Importantly, in comparison to small-molecule drug discovery, stapled peptides have shown the potential to achieve unique target family selectivity profiles that are of significant value for exploring intracellular mechanisms and/or to overcome known disease resistance mechanisms. One example of this includes the design of BID BH3, BIM BH3, BAD BH3 and Mcl-1 BH3 stapled helical peptides for Bcl-2 family targets 19,[22][23][24]43,47,58,[67][68][69][70][71]77,83,92,93,122 in which multi-specificity inclu...…”