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Stereochemistry and innate immune recognition: (+)‐norbinaltorphimine targets myeloid differentiation protein 2 and inhibits toll‐like receptor 4 signaling
Author(s) -
Zhang Xiaozheng,
Peng Yinghua,
Grace Peter M.,
Metcalf Matthew D.,
Kwilasz Andrew J.,
Wang Yibo,
Zhang Tianshu,
Wu Siru,
Selfridge Brandon R.,
Portoghese Philip S.,
Rice Kenner C.,
Watkins Linda R.,
Hutchinson Mark R.,
Wang Xiaohui
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201900173rrr
Subject(s) - tlr4 , innate immune system , toll like receptor , pharmacology , naltrexone , chemistry , cancer research , microbiology and biotechnology , receptor , biology , biochemistry , antagonist
ABSTRACT Deregulation of innate immune TLR4 signaling contributes to various diseases including neuropathic pain and drug addiction. Naltrexone is one of the rare TLR4 antagonists with good blood‐brain barrier permeability and showing no stereoselectivity for TLR4. By linking 2 naltrexone units through a rigid pyrrole spacer, the bivalent ligand norbinaltorphimine was formed. Interestingly, (+)‐norbinaltorphimine [(+)‐1] showed ∼25 times better TLR4 antagonist activity than naltrexone in microglial BV‐2 cell line, whereas (–)‐norbinaltorphimine [(–)‐1] lost TLR4 activity. The enantioselectivity of norbinaltorphimine was further confirmed in primary microglia, astrocytes, and macrophages. The activities of meso isomer of norbinaltorphimine and the molecular dynamic simulation results demonstrate that the stereochemistry of (+)‐1 is derived from the (+)‐naltrexone pharmacophore. Moreover, (+)‐1 significantly increased and prolonged morphine analgesia in vivo . The efficacy of (+)‐1 is long lasting. This is the first report showing enantioselective modulation of the innate immune TLR signaling.—Zhang, X., Peng, Y., Grace, P. M., Metcalf, M. D., Kwilasz, A. J., Wang, Y., Zhang, T., Wu, S., Selfridge, B. R., Portoghese, P. S., Rice, K. C., Watkins, L. R., Hutchinson, M. R., Wang, X. Stereochemistry and innate immune recognition: (+)‐norbinaltorphimine targets myeloid differentiation protein 2 and inhibits toll‐like receptor 4 signaling. FASEB J. 33,9577‐9587 (2019). www.fasebj.org