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Issue 1, 2013
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Phage display libraries of differently sized bicyclic peptides

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Phage selections with combinatorial libraries of uniformly sized bicyclic peptides have recently yielded potent and selective binders of several protein targets. In this work we varied in a combinatorial fashion the ring sizes of bicyclic peptides in phage libraries, expecting that they would yield binders with higher affinities and/or more diverse binding motifs that could be affinity matured. 14 new phage peptide libraries of the format Cys-(Xaa)m-Cys-(Xaa)n-Cys (Xaa are random amino acids, m and n = 3, 4, 5 or 6) were generated and cyclized with tris-(bromomethyl)benzene. Affinity selections against the tumor-associated serine protease urokinase-type plasminogen activator yielded bicyclic peptideinhibitors with a large variety of consensus sequences. Several of the identified consensus sequences were exclusively found in bicyclic peptides having defined ring size combinations. Some of these peptides may bind in orientations that allow affinity maturation of non-conserved regions, while others do not. Having available multiple leads isolated from such bicyclic peptide libraries with variable ring sizes could therefore be a great asset for the generation of high affinity binders.

Graphical abstract: Phage display libraries of differently sized bicyclic peptides

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Supplementary files

Article information

29 Jun 2012
17 Aug 2012
First published
17 Aug 2012

Med. Chem. Commun., 2013,4, 145-150
Article type
Concise Article

Phage display libraries of differently sized bicyclic peptides

I. R. Rebollo, A. Angelini and C. Heinis, Med. Chem. Commun., 2013, 4, 145
DOI: 10.1039/C2MD20171B

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