TM-PepStap2 · Transition metal catalysis for the generation of structurally minimal peptide staples

Peptide stapling (PS) is the process of generating macrocyclic peptides by chemically linking amino acid side-chains on a linear starting peptide. Stapling has been shown to confer favourable properties on its products, such as enhanced physiological stability and binding affinity for targets; however the inclusion of the 'staple' group has been suggested to lead to undesired interactions which can negatively impact the utility profile of these products.Herein we propose a pair of catalytic methodologies to be used for PS which would generate structurally minimal staples; these methodologies are known to be tolerant of conditions relevant to peptide chemistry. We propose to optimise for reactivity, selectivity, and efficiency on model substrates; explore the scope of the reactions by synthesising a library of model peptides; and finally validate the use of the developed technology by applying it to the synthesis of analogues of a MDM2-binding peptide and assessing the in vitro binding and stability properties of these products. This multidisciplinary project will encompass the scientific areas between organometallic chemistry and chemical biology, and has the potential to exert a gainful impact on the field of peptide therapeutic development.