Phosphocholine-Decorated PPI-Dendrimers Mimic Cell Membrane Phosphocholine Clusters and Tune the Innate Immune Activity of C-Reactive Protein

Ulrik Boas*, Mohammad Mahdi Daoud, Sebastian Meier, Tobias Hegelund Olsen, Kristoffer Gehring, Ditte Juhl Mogensen, Peter M. H. Heegaard

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

C-reactive protein (CRP) is a widely used as biomarker of infection and inflammation. It has a well-described ability to bind phosphocholine (PC), as well as PC-clusters from compromised and inflamed cell membranes and tissues. The binding of PC-clusters to CRP is of interest as this binding determines subsequent innate immune activity. We investigated PC-decorated dendrimers as mimics for PC-clusters. Five generations of poly(propylene imine) (PPI) dendrimers were modified with PC surface groups via a three-step synthetic sequence obtaining the PC decorated dendrimers in high purity. The dendrimers were analyzed by NMR and infrared spectroscopy as well as HPLC. We developed immunoassays to show that dendrimer-PC binding to CRP was Ca2+- dependent with an apparent overall Kd of 11.9 nM for first generation (G1) PPI-PC, while G2- and G3-PPI-PC had a slightly higher affinity, and G4 PPI-PC and G5-PPI-PC a slightly lower affinity. For all PC-dendrimers the affinity was orders of magnitude higher than the affinity of free phosphocholine (PC), indicating a PC-cluster effect. Next we investigated the binding of CRP:PPI-PC complexes to complement component C1q. C1q binding to CRP was dependent on the generation of PPI-PC bound to CRP, with second and third generation PPI-PC leading to the highest affinity. The dendrimer-based approach to PC-cluster mimics and the simple binding assays presented here hold promise as tools to screen PCcompounds for their ability to tune the innate immune activity of CRP.
Original languageEnglish
JournalBiomacromolecules
ISSN1525-7797
Publication statusAccepted/In press - 2021

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