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Oxadiazole grafts in peptide macrocycles

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Abstract

Synthetic methods that provide control over macrocycle conformation and, at the same time, mitigate the polarity of peptide bonds represent valuable tools for the discovery of new bioactive molecules. Here, we report a macrocyclization reaction between a linear peptide, an aldehyde and (N-isocyanimino)triphenylphosphorane. This process generates head-to-tail cyclic peptidomimetics in a single step. This method is tolerant to variation in the peptide and aldehyde components and has been applied for the synthesis of 15-, 18-, 21- and 24-membered rings. The resulting peptide macrocycles feature a 1,3,4-oxadiazole and a tertiary amine in their scaffolds. This non-canonical backbone region acts as an endocyclic control element that promotes and stabilizes a unique intramolecular hydrogen-bond network and can lead to macrocycles with conformationally rigid turn structures. Oxadiazole-containing macrocycles can also display a high passive membrane permeability, an important property for the development of bioavailable peptide-based therapeutics.

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Figure 1: Synthesis and characterization of oxadiazole-containing macrocyclic peptides.
Figure 2: Proposed reaction mechanism for macrocycle formation via zwitterionic control.
Figure 3: Contrasting the structural features of oxadiazole-containing macrocycles and homodetic counterparts.
Figure 4: Structural properties of oxadiazole-containing macrocycles.

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Change history

  • 04 November 2016

    In the version of this Article originally published the label 'Gly2' was mistakenly omitted from Fig. 3a. This has now been corrected online.

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Acknowledgements

We thank D. Burns and D. Pichugin for their assistance with NMR spectroscopic experiments and A. J. Lough for acquiring and solving X-ray crystal structures. A. L. Roughton (Encycle Therapeutics) is thanked for coordinating the PAMPA analysis and thoughtful discussions. This paper is dedicated to Professor G. K. Surya Prakash.

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A.K.Y. conceived the idea. J.R.F and C.C.G.S designed and performed the experiments and analysed the experimental data. J.R.F. prepared the manuscript with contributions from all the authors; all the authors contributed to discussions.

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Correspondence to Andrei K. Yudin.

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A.Y. is the scientific founder of Encycle Therapeutics.

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Crystallographic data for compound 1a (CIF 1165 kb)

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Frost, J., Scully, C. & Yudin, A. Oxadiazole grafts in peptide macrocycles. Nature Chem 8, 1105–1111 (2016). https://doi.org/10.1038/nchem.2636

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