Acylated heptapeptide binds albumin with high affinity and application as tag furnishes long-acting peptides

Alessandro Zorzi, Simon J. Middendorp, Jonas Wilbs, Kaycie Deyle and Christian Heinis ()
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Alessandro Zorzi: Institute of Chemical Sciences and Engineering, School of Basic Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Simon J. Middendorp: Institute of Chemical Sciences and Engineering, School of Basic Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Jonas Wilbs: Institute of Chemical Sciences and Engineering, School of Basic Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Kaycie Deyle: Institute of Chemical Sciences and Engineering, School of Basic Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Christian Heinis: Institute of Chemical Sciences and Engineering, School of Basic Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)

Nature Communications, 2017, vol. 8, issue 1, 1-9

Abstract: Abstract The rapid renal clearance of peptides in vivo limits this attractive platform for the treatment of a broad range of diseases that require prolonged drug half-lives. An intriguing approach for extending peptide circulation times works through a ‘piggy-back’ strategy in which peptides bind via a ligand to the long-lived serum protein albumin. In accordance with this strategy, we developed an easily synthesized albumin-binding ligand based on a peptide-fatty acid chimera that has a high affinity for human albumin (Kd=39 nM). This ligand prolongs the elimination half-life of cyclic peptides in rats 25-fold to over seven hours. Conjugation to a peptide factor XII inhibitor developed for anti-thrombotic therapy extends the half-life from 13 minutes to over five hours, inhibiting coagulation for eight hours in rabbits. This high-affinity albumin ligand could potentially extend the half-life of peptides in human to several days, substantially broadening the application range of peptides as therapeutics.

Date: 2017
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DOI: 10.1038/ncomms16092

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