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  • Multivalent site-specific phage modification enhances the binding affinity of receptor ligands.

Multivalent site-specific phage modification enhances the binding affinity of receptor ligands.

Bioconjugate chemistry (2015-02-19)
Jaymes Beech, Lana Saleh, Julie Frentzel, Heidi Figler, Ivan R Corrêa, Brenda Baker, Caroline Ramspacher, Melissa Marshall, Siva Dasa, Joel Linden, Christopher J Noren, Kimberly A Kelly
ABSTRACT

High-throughput screening of combinatorial chemical libraries is a powerful approach for identifying targeted molecules. The display of combinatorial peptide libraries on the surface of bacteriophages offers a rapid, economical way to screen billions of peptides for specific binding properties and has impacted fields ranging from cancer to vaccine development. As a modification to this approach, we have previously created a system that enables site-specific insertion of selenocysteine (Sec) residues into peptides displayed pentavalently on M13 phage as pIII coat protein fusions. In this study, we show the utility of selectively derivatizing these Sec residues through the primary amine of small molecules that target a G protein-coupled receptor, the adenosine A1 receptor, leaving the other coat proteins, including the major coat protein pVIII, unmodified. We further demonstrate that modified Sec-phage with multivalent bound agonist binds to cells and elicits downstream signaling with orders of magnitude greater potency than that of unconjugated agonist. Our results provide proof of concept of a system that can create hybrid small molecule-containing peptide libraries and open up new possibilities for phage-drug therapies.

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