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Bicyclization and Tethering to Albumin Yields Long-Acting Peptide Antagonists

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Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
*Tel: +41(0)21 693 9350. E-mail: [email protected]
Cite this: J. Med. Chem. 2012, 55, 22, 10187–10197
Publication Date (Web):October 22, 2012
Copyright © 2012 American Chemical Society

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    Proteolytically stable peptide architectures are required for the development of long-acting peptide therapeutics. In this work, we found that a phage-selected bicyclic peptide antagonist exhibits an unusually high stability in vivo and subsequently deciphered the underlying mechanisms of peptide stabilization. We found that the bicyclic peptide was significantly more stable than its constituent rings synthesized as two individual macrocycles. The two rings protect each other from proteolysis when linked together, conceivably by constraining the conformation and/or by mutually shielding regions prone to proteolysis. A second stabilization mechanism was found when the bicyclic peptide was linked to an albumin-binding peptide to prevent its rapid renal clearance. The bicyclic peptide conjugate not only circulated 50-fold longer (t1/2 = 24 h) but also became entirely resistant to proteolysis when tethered to the long-lived serum protein. The bicyclic peptide format overcomes a limitation faced by many peptide leads and appears to be suitable for the generation of long-acting peptide therapeutics.

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    Supplementary figures showing the synthesis strategies of the peptide conjugates and figures showing experimental data from the peptide binding, inhibition, and stability assays. This material is available free of charge via the Internet at

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