From Phage Display to Dendrimer Display: Insights into Multivalent Binding

Maartje M. C. Bastings, Brett A. Helms, Ingrid van Baal, Tilman M. Hackeng, Maarten A. G. Merkx, E. W. Meijer*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

27 Citations (Web of Science)

Abstract

Phage display is widely used for the selection of target-specific peptide sequences. Presentation of phage peptides on a multivalent platform can be used to (partially) restore the binding affinity. Here, we present a detailed analysis of the effects of valency, linker choice, and receptor density on binding affinity of a multivalent architecture, using streptavidin (SA) as model multivalent receptor. For surfaces with low receptor densities, the SA binding affinity of multivalent dendritic phage peptide constructs increases over 2 orders of magnitude over the monovalent species (e.g., K(d,mono) = 120 mu M vs K(d,tetra) = 1 mu M), consistent with previous work. However, the affinity of the SA-binding phage presenting the exact same peptides was 16 pM when dense receptor surfaces used for initial phage display were used in assays. The phage affinity for SA-coated surfaces weakens severely toward the nanomolar regime when surface density of SA is decreased. A similarly strong dependence in this respect was observed for dendritic phage analogues. When presented with a dense SA-coated surface, dendrimer display affords up to a 10(4)-fold gain in affinity over the monovalent peptide. The interplay between ligand valency and receptor density is a fundamental aspect of multivalent targeting strategies in biological systems. The perspective offered here suggests that in vivo targeting schemes might best be served to conduct ligand selection under physiologically relevant receptor density surfaces, either by controlling the receptor density placed at the selection surface or by using more biologically relevant intact cells and tissues.
Original languageEnglish
Pages (from-to)6636-6641
JournalJournal of the American Chemical Society
Volume133
Issue number17
DOIs
Publication statusPublished - 4 May 2011

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