Abstract
Ligands selected from phage-displayed random peptide libraries tend to be directed to biologically relevant sites on the surface of the target protein. Consequently, peptides derived from library screenings often modulate the target protein’s activity in vitro and in vivo and can be used as lead compounds in drug design and as alternatives to antibodies for target validation in both genomics and drug discovery. This review discusses the use of phage display to identify membrane receptor modulators with agonistic or antagonistic activities. Because isolating or producing recombinant membrane proteins for use as target molecules in library screening is often impossible, innovative selection strategies such as panning against whole cells or tissues, recombinant receptor ectodomains, or neutralizing antibodies to endogenous binding partners were devised. Prominent examples from a two-decade history of peptide phage display will be presented, focusing on the design of affinity selection experiments, methods for improving the initial hits, and applications of the identified peptides.
Highlights
Phage display technology is based on the ability to express foreignpeptides as fusions to capsid proteins on the surface of bacteriophage and was first described in 1985 by George P
Combined with rational drug design, the screening of combinatorial peptide libraries against membrane receptors is a powerful tool for discovering novel pharmacologically active receptor agonists and antagonists or small peptide ligands for the targeted delivery of drugs, genes and diagnostics
Two of the earliest and probably most prominent reports of the identification of potent agonistic peptides by phage library screening were contributed by Wrighton et al [6] and Cwirla et al [7] for the erythropoietin receptor (EpoR) and thrombopoietin receptor (TpoR), respectively
Summary
Phage display technology is based on the ability to express foreign (poly)peptides as fusions to capsid proteins on the surface of bacteriophage and was first described in 1985 by George P. Novagen’s system T7Select for display of peptides and proteins on the capsid of lytic phage T7 offers the option of adjusting display valency to one’s needs by choosing among phage vectors T7Select-1, -10, and -415 (low, intermediate, and high copy display vectors, respectively) in which major coat protein-peptide fusion genes are transcriptionally controlled by diverse regulatory elements [26]. Combined with rational drug design, the screening of combinatorial peptide libraries against membrane receptors is a powerful tool for discovering novel pharmacologically active receptor agonists and antagonists or small peptide ligands for the targeted delivery of drugs, genes and diagnostics. We review selection strategies for screening phage-displayed random peptide libraries, focusing on the different approaches that have been implemented to make the technology applicable to the selection of membrane receptor ligands. We discuss how primary screening hits can be optimized for downstream applications
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