Stereochemistry and innate immune recognition: (+)-norbinaltorphimine targets myeloid differentiation protein 2 and inhibits toll-like receptor 4 signaling

Xiaozheng Zhang, Yinghua Peng, Peter M. Grace, Matthew D. Metcalf, Andrew J. Kwilasz, Yibo Wang, Tianshu Zhang, Siru Wu, Brandon R. Selfridge, Philip S Portoghese, Kenner C. Rice, Linda R. Watkins, Mark R. Hutchinson, Xiaohui Wang

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)9577-9587
Number of pages11
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume33
Issue number8
DOIs
StatePublished - Aug 1 2019

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Stereochemistry
Toll-Like Receptor 4
Naltrexone
Proteins
Stereoselectivity
Pyrroles
Deregulation
Macrophages
Enantioselectivity
Microglia
Neuralgia
Molecular Dynamics Simulation
Blood-Brain Barrier
Astrocytes
Isomers
Analgesia
Morphine
Substance-Related Disorders
Molecular dynamics
norbinaltorphimine

Keywords

  • MD-2
  • TLR4
  • enantioselective modulation
  • morphine analgesia
  • norbinaltorphimine

PubMed: MeSH publication types

  • Journal Article

Cite this

Stereochemistry and innate immune recognition : (+)-norbinaltorphimine targets myeloid differentiation protein 2 and inhibits toll-like receptor 4 signaling. / 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.

In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Vol. 33, No. 8, 01.08.2019, p. 9577-9587.

Research output: Contribution to journalArticle

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. / Stereochemistry and innate immune recognition : (+)-norbinaltorphimine targets myeloid differentiation protein 2 and inhibits toll-like receptor 4 signaling. In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2019 ; Vol. 33, No. 8. pp. 9577-9587.
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AU - Kwilasz, Andrew J.

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AU - Zhang, Tianshu

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