TY - JOUR
T1 - Highly Effective Poly(Ethylene Glycol) Architectures for Specific Inhibition of Immune Receptor Activation
AU - Baird, Emily J.
AU - Holowka, David
AU - Coates, Geoffrey W.
AU - Baird, Barbara
PY - 2003/11/11
Y1 - 2003/11/11
N2 - Architectural features of synthetic ligands were systematically varied to optimize inhibition of mast cell degranulation initiated by multivalent crossing of IgE-receptor complexes. A series of ligands were generated by end-capping poly(ethylene glycol) (PEG) polymers and amine-based dendrimers with the hapten 2,4-dinitrophenyl (DNP). These were used to explore the influence of polymeric backbone length, valency, and hapten presentation on binding to anti-DNP IgE and inhibition of stimulated activation of RBL cells. Monovalent MPEG5000-DNP (IC50 = 50 nM), bivalent DNP-PEG3350-DNP (IC50 = 8 nM), bismonovalent MPEG 5000-DNP2 (IC50 = 20 nM), bisbivalent DNP 2-PEG3350-DNP2 (IC50 = 3nM) and DNP4-dendrimer ligands (IC50 = 50 nM) all effectively inhibit cellular activation caused by multivalent antigen, DNP-bovine serum albumin. For different DNP ligands, we provide evidence for more effective inhibition due to (i) preferential formation of intra-IgE cross-links by bivalent ligands of sufficient length, (ii) self-association of monovalent ligands with longer tails, and (iii) higher probability of binding for bisvalent ligands. We also show that larger DNP16-dendrimers of higher valency trigger degranulation by cross-linking IgE-receptor complexes, whereas smaller DNP-dendrimers are inhibitory. Thus, features of synthetic ligands can be manipulated to control receptor occupation, aggregation, and inhibition of the cellular response.
AB - Architectural features of synthetic ligands were systematically varied to optimize inhibition of mast cell degranulation initiated by multivalent crossing of IgE-receptor complexes. A series of ligands were generated by end-capping poly(ethylene glycol) (PEG) polymers and amine-based dendrimers with the hapten 2,4-dinitrophenyl (DNP). These were used to explore the influence of polymeric backbone length, valency, and hapten presentation on binding to anti-DNP IgE and inhibition of stimulated activation of RBL cells. Monovalent MPEG5000-DNP (IC50 = 50 nM), bivalent DNP-PEG3350-DNP (IC50 = 8 nM), bismonovalent MPEG 5000-DNP2 (IC50 = 20 nM), bisbivalent DNP 2-PEG3350-DNP2 (IC50 = 3nM) and DNP4-dendrimer ligands (IC50 = 50 nM) all effectively inhibit cellular activation caused by multivalent antigen, DNP-bovine serum albumin. For different DNP ligands, we provide evidence for more effective inhibition due to (i) preferential formation of intra-IgE cross-links by bivalent ligands of sufficient length, (ii) self-association of monovalent ligands with longer tails, and (iii) higher probability of binding for bisvalent ligands. We also show that larger DNP16-dendrimers of higher valency trigger degranulation by cross-linking IgE-receptor complexes, whereas smaller DNP-dendrimers are inhibitory. Thus, features of synthetic ligands can be manipulated to control receptor occupation, aggregation, and inhibition of the cellular response.
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U2 - 10.1021/bi034884l
DO - 10.1021/bi034884l
M3 - Article
C2 - 14596588
AN - SCOPUS:0242507493
SN - 0006-2960
VL - 42
SP - 12739
EP - 12748
JO - Biochemistry
JF - Biochemistry
IS - 44
ER -