Abstract
Constraining a peptide in its bioactive conformation by macrocyclization represents a powerful strategy to design modulators of challenging biomolecular targets. This holds particularly true for the development of inhibitors of protein-protein interactions which often involve interfaces lacking defined binding pockets. Such flat surfaces are demanding targets for traditional small molecules rendering macrocyclic peptides promising scaffolds for novel therapeutics. However, the contribution of peptide dynamics to binding kinetics is barely understood which impedes the design process. Herein, we report unexpected trends in the binding kinetics of two closely related macrocyclic peptides that bind their receptor protein with high affinity. Isothermal titration calorimetry, 19F NMR experiments and molecular dynamics simulations reveal that increased conformational flexibility of the macrocycle–receptor complex reduces dissociation rates and contributes to complex stability. This observation has impact on macrocycle design strategies that have so far mainly focused on the stabilization of bioactive ligand conformations.
Original language | English |
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Pages (from-to) | 16157-16161 |
Number of pages | 5 |
Journal | Chemistry - A European Journal |
Volume | 23 |
Issue number | 64 |
DOIs | |
Publication status | Published - 16 Nov 2017 |
Funding
This work was supported by the German Research Foundation (DFG, Emmy Noether program RA1944/2-1 and GR3592/2-1) and the European Research Council (ERC starting grant, no. 678623). We are also grateful for support by AstraZeneca, Bayer CropScience, Bayer HealthCare, Boehringer Ingelheim, Merck KGaA, and the Max Planck Society.
Funders | Funder number |
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AstraZeneca | |
Boehringer Ingelheim | |
Bayer CropScience | |
Merck KGaA | |
Horizon 2020 Framework Programme | 678623 |
European Research Council | |
Bayer HealthCare | |
Deutsche Forschungsgemeinschaft | GR3592/2-1, RA1944/2-1 |
Max-Planck-Gesellschaft |
Keywords
- F NMR spectroscopy
- binding kinetics
- cyclic peptides
- molecular dynamics simulation
- peptidomimetics