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Design and Development of a Cyclic Decapeptide Scaffold with Suitable Properties for Bioavailability and Oral Exposure

Fouche, Marianne, Roth, Hans-Joerg, Schaefer, Michael, Berghausen, Joerg, Desrayaud, Sandrine, Blatter, Markus, Piechon, Philippe, Dix, Ina and Martin Garcia, Aimar (2016) Design and Development of a Cyclic Decapeptide Scaffold with Suitable Properties for Bioavailability and Oral Exposure. ChemMedChem.


Permeability and oral bioavailability of macrocyclic peptides still represents a difficult challenge in drug discovery. Despite their recognised potential as therapeutics, their use is still restricted to extra-cellular targets and i.v. administration. Indeed, macrocyclic peptides generally suffer from limited proteolytic stability, high clearance and poor membrane permeability leading to the absence of systemic exposure after oral administration. In order to overcome these limitations, we started to investigate the development of a general cyclic decapeptide scaffold that possesses ideal features for cell permeability and oral exposure. Based on a hairpin structure, the scaffold design aimed to reduce the overall polarity of the compound thereby limiting the energetic cost of NH desolvation and the entropy penalty during cell penetration. The results of this study demonstrate the importance of rigidity for the -turn design regarding clearance. In order to stabilize the scaffold in the desired β-hairpin conformation to favour permeability, the introduction of D-proline at the i+1 turn position also proved to be beneficial in limiting clearance. As a result, cyclopeptide decamers with unprecedented high values for oral bioavailability and exposure are reported herein. NMR conformation and dynamic analysis confirmed for selected examples the rigidity of the scaffold and the presence of trans-annular hydrogen bonds in polar and apolar environments. Furthermore, we showed that the excellent bioavalability value obtained for one compound was supported by a favourable entropy for the transition from a polar to an apolar environment.

Item Type: Article
Date Deposited: 19 May 2016 23:45
Last Modified: 29 Jun 2016 23:45


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