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FASEB J. 2019 Jun 4:fj201900173RRR. doi: 10.1096/fj.201900173RRR. [Epub ahead of print]

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

Author information

1
Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
2
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
3
University of Chinese Academy of Sciences, Beijing, China.
4
State Key Laboratory for Molecular Biology of Special Economic Animals, Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, China.
5
Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado at Boulder, Boulder, Colorado, USA.
6
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.
7
Drug Design and Synthesis Section, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
8
Discipline of Physiology, Adelaide Medical School and Australian Research Council (ARC) Centre of Excellence for Nanoscale Biophotonics, University of Adelaide, South Australia, Australia.
9
Department of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, China.

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 microglia 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.

KEYWORDS:

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

PMID:
31162938
DOI:
10.1096/fj.201900173RRR

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