Structural insights reveal a recognition feature for tailoring hydrocarbon stapled-peptides against the eukaryotic translation initiation factor 4E protein. Issue 8 (15th January 2019)

• Record Type: Journal Article
• Authors: Lama, Dilraj; Liberatore, Anne-Marie; Frosi, Yuri; Nakhle, Jessica; Tsomaia, Natia; Bashir, Tarig; Lane, David P.; Brown, Christopher J.; Verma, Chandra S.; Auvin, Serge
• Is Part Of: Chemical science. Volume 10:Issue 8(2019)
• Page Start: 2489
• Page End: 2500
• Publication Date: 2019-01-15
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c8sc03759k
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : We have revealed a non-canonical recognition feature that can modulate the binding kinetics of hydrocarbon stapled-peptides interactions with the eIF4E protein. Abstract : Stapled-peptides have emerged as an exciting class of molecules which can modulate protein–protein interactions. We have used a structure-guided approach to rationally develop a set of hydrocarbon stapled-peptides with high binding affinities and residence times against the oncogenic eukaryotic translation initiation factor 4E (eIF4E) protein. Crystal structures of these peptides in complex with eIF4E show that they form specific interactions with a region on the protein-binding interface of eIF4E which is distinct from the other well-established canonical interactions. This recognition element is a major molecular determinant underlying the improved binding kinetics of these peptides with eIF4E. The interactions were further exploited by designing features in the peptides to attenuate disorder and increase helicity which collectively resulted in the generation of a distinct class of hydrocarbon stapled-peptides targeting eIF4E. This study details new insights into the molecular basis of stapled-peptide: eIF4E interactions and their exploitation to enhance promising lead molecules for the development of stapled-peptide compounds for oncology.