Structure based design of bicyclic peptide inhibitors of RbAp48

Adihou H, 't Hart P, Hommen P, Noisier A, Krzyzanowski A, Schüler D, Porfetye AT, Akbarzadeh M, Vetter IR, Waldmann H (2020) Angew Chem Int Ed Engl

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The Waldmann Group together with Dr. Helene Adihou from the Astra Zeneca Satellite Unit and the group of Dr. Ingrid Vetter and Dr. Peter 't Hart have developed peptide inhibitors targeting the protein-protein interaction interface between RbAp48 and the scaffold protein MTA1. Based on a MTA1-derived linear peptide with low micromolar affinity and informed by crystallographic analysis, a bicyclic peptide was developed that inhibits the RbAp48/MTA1 interaction with a very low nanomolar KD value of 8.56 nM, and which showed appreciable stability against cellular proteases. Design included exchange of a polar amide cyclization strategy to hydrophobic aromatic linkers enabling mono- and bicyclization by means of cysteine alkylation, which improved affinity by direct interaction of the linkers with a hydrophobic residue on RbAp48. Our results demonstrate that stepwise evolution of a structure-based design is a suitable strategy for inhibitor development targeting PPIs.

Development of the potent bicyclic peptide inhibitors of the RbAp48-MTA1 interaction by structure based stepwise optimization of the cyclization linker.
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