Design of a superior cytokine antagonist for topical ophthalmic use
| Autor: | Gregory Zarbis-Papastoitsis, Allyson Masci, Christoph Thomas, Sharon A. Townson, Olga Kiner, Kathryn Golden, Jinzhao Hou, Joseph Kovalchin, Yanqun Shu, Emily Belcher Schirmer, Eric Furfine, K. Christopher Garcia, Thomas M. Barnes, Bracken M. King |
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| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular Protein Conformation medicine.drug_class Administration Topical Recombinant Fusion Proteins medicine.medical_treatment Interleukin-1beta Molecular Sequence Data Static Electricity Pharmacology Biology Crystallography X-Ray Ligands Mice Mediator Immune system Drug Stability In vivo medicine Animals Humans Amino Acid Sequence Receptor Receptors Interleukin-1 Type I Multidisciplinary Sequence Homology Amino Acid Antagonist Biological Sciences Receptor antagonist Mice Inbred C57BL Interleukin 1 Receptor Antagonist Protein Kinetics Cytokine Drug Design Cytokines Female Ophthalmic Solutions Decoy |
| Zdroj: | Proceedings of the National Academy of Sciences. 110:3913-3918 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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-1 receptor ligands, IL-1β and IL-1Ra, 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-1Ra, and this increase translates to an ∼100-fold increase in potency in vivo. EBI-005 preserves the affinity bias of IL-1Ra for IL-1R1 over the decoy receptor (IL-1R2), 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-1 and FGF families. |
| Databáze: | OpenAIRE |
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