Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
Stapled-peptides targeting the protein-binding interface of eukaryotic Translation Initiation Factor 4E (eIF4E) protein
Targeting undruggable protein-protein interacting sites has received a promising boost with the developments of an emerging class of peptidomimetics called stapled-peptides (Verdine & Hilinski, 2012). These peptides are designed by attachment of a hydrocarbon linker yielding higher affinities, better cellular permeability and protection against proteosomal degradation. We describe here the development of stapled-peptides against the eIF4E protein, combining extensive modelling, molecular dynamics simulations, structural and biophysical studies (Lama et. al., 2013, Figure below). This protein is involved in the initial step of mRNA recognition and subsequent translation and is frequently overexpressed in large number of cancers, thus rendering it as a potential druggable target. Initially, a set of peptides were rationally designed, modelled and investigated for their behaviour in solution and in complex with the protein. We observed that stapling influences the affinity of the peptides for eIF4E by modulating both the properties of the peptide and the binding interface of the complex. The information obtained from this initial study was used to further optimise the originally designed stapled-peptides by rationally introducing mutations and confirming the models through crystallographic studies. This finally led to the development of nanomolar binders that have affinities similar to or higher than their linear counterparts. The findings from this work will enhance the development of potential peptide-based lead compounds against eIF4E and also provide greater understanding of the effects of incorporating staples into peptides targeting protein: protein interfaces.
This research was supported by A*PRE*COT (PRE-COT 2010-04) grant.
Lama D., Quah S. T., Verma C.S., Lakshminarayanan R., Beuerman R. W., Lane D. P., & Brown C. J. (2013). Rational optimization of conformational effects induced by hydrocarbon staples in peptides and their binding interfaces Scientific Reports 3, 3451.
1 Bioinformatics Institute,