Development of an IL-6 Inhibitor Based on the Functional Analysis of Murine IL-6Rα1

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Abstract

Dysregulated cytokine production contributes to inflammatory and proliferative diseases. Therefore, inhibition of proinflammatory mediators such as TNF, IL-1, and IL-6 is of great clinical relevance. Actual strategies are aimed at preventing receptor activation through sequestration of the ligand. Here we describe the development of an inhibitor of murine IL-6 based on fused receptor fragments. Molecular modeling-guided analysis of the murine IL-6Rα revealed that mutations in the Ig-like domain D1 severely affect protein function, although D1 is not directly involved in the ligand-binding interface. The resulting single chain IL-6 inhibitor (mIL-6-RFP) consisting of domains D1-D3 of mgp130, a flexible linker, and domains D1-D3 of mIL-6Rα is a highly potent and specific IL-6 inhibitor. mIL-6-RFP will permit further characterization of the role of IL-6 in various disease models and could ultimately lead to anti-IL-6 therapy. © 2009 Elsevier Ltd. All rights reserved.

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Wiesinger, M. Y., Haan, S., Wüller, S., Kauffmann, M. E., Recker, T., Küster, A., … Müller-Newen, G. (2009). Development of an IL-6 Inhibitor Based on the Functional Analysis of Murine IL-6Rα1. Chemistry and Biology, 16(7), 783–794. https://doi.org/10.1016/j.chembiol.2009.06.010

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