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Multivalent Tethered Ligands Enhance Cell Targeting Specificity and Reactivity
Author(s) -
Weber Craig,
Vagner Josef,
Xu Liping,
Gillies Robert,
Lynch Ronald
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.1026.1
Subject(s) - receptor , cholecystokinin , cell , chemistry , linker , ligand (biochemistry) , cholecystokinin receptor , microbiology and biotechnology , binding selectivity , biophysics , biochemistry , biology , computer science , operating system
Specific cells types can be identified by markers expressed on their surfaces (e.g., receptors). Ligands for single receptors usually do not provide enough specificity for targeting only the cell type of interest, particularly for cells found in low number. However, targeting a combination of surface markers may greatly enhance specificity. To test this, we developed a multivalent ligand (MVL) of melanocyte stimulating hormone (MSH) and cholecystokinin (CCK) linked together, then evaluated the binding affinity, specificity and activity of this agent. Relative to monvalent MSH or CCK the apparent binding affinity of the multivalent MSH‐CCK was enhanced ~80 fold. To obtain this enhanced binding, the linker length needed to be greater than ~80 atoms of polyethyleneglycol. This MVL clearly distinguished cells expressing both receptors from those expressing only CCK or MC receptors, at low concentrations (<0.4 nM) demonstrating elevated specificity. Within 10 minutes of incubation, the MVL was capped and endocytosed from the cell surface. Moreover, the MVL of MSH‐CCK exhibited CCK like activity (elevation of cell Ca2+), but at concentrations 10X less than required for CCK activation. This work lays the foundation for further development and detailed study of a range of multimeric ligands to enhance cell specific targeting, and activation.