Phage display and selection of lanthipeptides on the carboxy-terminus of the gene-3 minor coat protein

Johannes H. Urban (), Markus A. Moosmeier, Tobias Aumüller, Marcus Thein, Tjibbe Bosma, Rick Rink, Katharina Groth, Moritz Zulley, Katja Siegers, Kathrin Tissot, Gert N. Moll and Josef Prassler
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Johannes H. Urban: MorphoSys AG, Semmelweisstr. 7
Markus A. Moosmeier: MorphoSys AG, Semmelweisstr. 7
Tobias Aumüller: MorphoSys AG, Semmelweisstr. 7
Marcus Thein: MorphoSys AG, Semmelweisstr. 7
Tjibbe Bosma: Lanthio Pharma, Rozenburglaan 13 B
Rick Rink: Lanthio Pharma, Rozenburglaan 13 B
Katharina Groth: MorphoSys AG, Semmelweisstr. 7
Moritz Zulley: MorphoSys AG, Semmelweisstr. 7
Katja Siegers: MorphoSys AG, Semmelweisstr. 7
Kathrin Tissot: MorphoSys AG, Semmelweisstr. 7
Gert N. Moll: Lanthio Pharma, Rozenburglaan 13 B
Josef Prassler: MorphoSys AG, Semmelweisstr. 7

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: Abstract Ribosomally synthesized and post-translationally modified peptides (RiPPs) are an emerging class of natural products with drug-like properties. To fully exploit the potential of RiPPs as peptide drug candidates, tools for their systematic engineering are required. Here we report the engineering of lanthipeptides, a subclass of RiPPs characterized by multiple thioether cycles that are enzymatically introduced in a regio- and stereospecific manner, by phage display. This was achieved by heterologous co-expression of linear lanthipeptide precursors fused to the widely neglected C-terminus of the bacteriophage M13 minor coat protein pIII, rather than the conventionally used N-terminus, along with the modifying enzymes from distantly related bacteria. We observe that C-terminal precursor peptide fusions to pIII are enzymatically modified in the cytoplasm of the producing cell and subsequently displayed as mature cyclic peptides on the phage surface. Biopanning of large C-terminal display libraries readily identifies artificial lanthipeptide ligands specific to urokinase plasminogen activator (uPA) and streptavidin.

Date: 2017
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DOI: 10.1038/s41467-017-01413-7

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