FLoS: Medicinal Chemistry & Chemical Biology, Short talk
FLoS-MC-03

Development of orally available peptide macrocycles by phage display    

X. Kong1, C. Heinis1*
1Laboratory of Therapeutic Proteins and Peptides (LPPT), Institute of Chemical Sciences and Engineering EPF Lausanne, BCH 5207, 1015 Lausanne

A major challenge in the pharmaceutical industry is the development of orally available peptide-based therapeutics.1 The oral delivery of protein and peptide drugs is mainly limited by their proteolytic degradation and the poor absorption across the intestinal epithelia.2 In this work, we have developed a method for the screening of proteolytic-resistant peptide macrocycles by phage display. In brief, peptides displayed on phage are cyclized in a chemical reaction, exposed to pancreatic proteases, and subjected to affinity selections. Affinity selections against the therapeutic target Factor XIa yielded potent inhibitors with Kis below 10 nM. Due to the protease pressure during phage display, the peptide macrocycles showed half-lifes of > 2 hours in presence of intestinal proteases at physiological concentration (10 mg/mL). Work is ongoing to test the oral availability of the cyclic peptide Factor XIa inhibitor in mice.    

[1] K. Fosgerau and T. Hoffmann, Drug Discovery Today, 2015. 20, 122-128.
[2] J. Wang, V. Yadav, A. L. Smart, S. Tajiri, A. W. Basit, Molecular Pharmaceutics, 2015, 12, 966-973.