An amber obligate active site-directed ligand evolution technique for phage display

Jeffery M. Tharp, J. Trae Hampton, Catrina A. Reed, Andreas Ehnbom, Peng-Hsun Chase Chen, Jared S. Morse, Yadagirri Kurra, Lisa M. Pérez, Shiqing Xu () and Wenshe Ray Liu ()
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Jeffery M. Tharp: Texas A&M University
J. Trae Hampton: Texas A&M University
Catrina A. Reed: Texas A&M University
Andreas Ehnbom: Texas A&M University
Peng-Hsun Chase Chen: Texas A&M University
Jared S. Morse: Texas A&M University
Yadagirri Kurra: Texas A&M University
Lisa M. Pérez: Texas A&M University
Shiqing Xu: Texas A&M University
Wenshe Ray Liu: Texas A&M University

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Although noncanonical amino acids (ncAAs) were first incorporated into phage libraries through amber suppression nearly two decades ago, their application for use in drug discovery has been limited due to inherent library bias towards sense-containing phages. Here, we report a technique based on superinfection immunity of phages to enrich amber-containing clones, thus avoiding the observed bias that has hindered incorporation of ncAAs into phage libraries. We then take advantage of this technique for development of active site-directed ligand evolution of peptides, where the ncAA serves as an anchor to direct the binding of its peptides to the target’s active site. To demonstrate this, phage-displayed peptide libraries are developed that contain a genetically encoded butyryl lysine and are subsequently used to select for ligands that bind SIRT2. These ligands are then modified to develop low nanomolar inhibitors of SIRT2.

Date: 2020
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DOI: 10.1038/s41467-020-15057-7

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