Rationally designed macrocyclic peptides as synergistic agonists of LPS-induced inflammatory response |
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| Authors: | Meng Gao Nir London Kui Cheng Ryo Tamura Jialin Jin Ora Schueler-Furman Hang Yin |
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| Affiliation: | 1. Center of Basic Molecular Science and Department of Chemistry, Tsinghua University, Beijing 100082, China;2. Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Hadassah Medical School, The Hebrew University, POB 12272, Jerusalem 91120, Israel;3. Department of Chemistry and Biochemistry, the BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80309-0596, USA |
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| Abstract: | Toll-like receptor 4 (TLR4) plays an important role in the regulation of the innate and adaptive immune response. Both agonists and antagonists of TLR4 are of considerable interest as drug leads for various disease indications. We herein report the rational design of two myeloid differentiation factor 2 (MD2)-derived macrocyclic peptides as TLR4 modulators, using the Rosetta Macromolecular Modeling software. The designed cyclic peptides, but not their linear counterparts, displayed synergistic activation of TLR signaling when co-administered with lipopolysaccharide (LPS). Although the understanding of the mechanism of action of these peptides remains elusive, these results underscore the utility of peptide cyclization for the discovery of biologically active agents, and also provide valuable tools for the investigation of TLR4 signaling. |
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| Keywords: | Macrocyclic peptide Toll-like receptor 4 Myeloid differentiation factor 2 Computational design Drug synergy |
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