| Autor: |
Jinzhao Hou, Townson, Sharon A., Kovaichin, Joseph T., Masci, Allyson, Kiner, Olga, Yanqun Shu, King, Bracken M., Schirmer, Emily, Golden, Kathryn, Thomas, Christoph, Garcia, K. Christopher, Zarbis-Papastoitsis, Gregory, Furfine, Eric S., Barnes, Thomas M. |
| Předmět: |
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| Zdroj: |
Proceedings of the National Academy of Sciences of the United States of America; 3/5/2013, Vol. 110 Issue 10, p3913-3918, 6p |
| Abstrakt: |
IL-1 is a key inflammatory and immune mediator in many diseases, including dry-eye disease, and its inhibition is clinically efficacious in rheumatoid arthritis and cryopyrin-associated periodic syndromes. To treat ocular surface disease with a topical biotherapeutic, the uniqueness of the site necessitates consideration of the agent's size, target location, binding kinetics, and thermal stability. Here we chimerized two IL-i receptor ligands, IL-iD and IL-iRa, to create an optimized receptor antagonist, EBI-005, for topical ocular administration. EBI-005 binds its target, IL-1R1, 85-fold more tightly than IL-iRa, and this increase translates to an ~100-fold increase in potency in vivo. EBI-005 preserves the affinity bias of IL-i Ra for IL-i Ri over the decoy receptor (IL-iR2), and, surprisingly, is also more thermally stable than either parental molecule. This rationally designed antagonist represents a unique approach to therapeutic design that can potentially be exploited for other β-trefoil family proteins in the IL-i and FGF families. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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