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

doi:10.1096/fj.201900173RRR

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

Medicinal Chemistry

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

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.

Original language	English (US)
Pages (from-to)	9577-9587
Number of pages	11
Journal	FASEB Journal
Volume	33
Issue number	8
DOIs	https://doi.org/10.1096/fj.201900173RRR
State	Published - Aug 1 2019

Bibliographical note

Funding Information:
The authors thank the Drug Supply Program of National Institute of Drug Abuse (Bethesda, MD, USA) for providing (−)-norbinaltorphimine. The authors also thank the Network and Coumputing Center, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, National Supercomputer Center of China in Guangzhou and the Computing Center of Jilin Province for the supply of computational resources. This work was supported by the National Key Research and Development Program of China (2016YFC0800907), the National Natural Science Foundation of China (21850410455, 21750110432, 21877106), the 100 Talents Program of Chinese Academy of Sciences, Young Talents Program of Chinese Academy of Agricultural Sciences, Central Public-interest Scientific Institution Basal Research Fund (NO.1610342016013), Natural Science Foundation of Jilin Province (20180101021JC), Open Fund of State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University (Grant No. KF-GN-201601), and U.S. National Institutes of Health (NIH) National Institute of Dental and Craniofacial Research Grant R01 DE017782 (to L.R.W.). The authors declare no conflicts of interest.

Publisher Copyright:
© FASEB

Keywords

MD-2
TLR4
enantioselective modulation
morphine analgesia
norbinaltorphimine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1096/fj.201900173RRR

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988860

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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. (2019). Stereochemistry and innate immune recognition: (+)-norbinaltorphimine targets myeloid differentiation protein 2 and inhibits toll-like receptor 4 signaling. FASEB Journal, 33(8), 9577-9587. https://doi.org/10.1096/fj.201900173RRR

Zhang, X, Peng, Y, Grace, PM, Metcalf, MD, Kwilasz, AJ, Wang, Y, Zhang, T, Wu, S, Selfridge, BR, Portoghese, PS, Rice, KC, Watkins, LR, Hutchinson, MR & Wang, X 2019, 'Stereochemistry and innate immune recognition: (+)-norbinaltorphimine targets myeloid differentiation protein 2 and inhibits toll-like receptor 4 signaling', FASEB Journal, vol. 33, no. 8, pp. 9577-9587. https://doi.org/10.1096/fj.201900173RRR

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

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.",

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

note = "Funding Information: The authors thank the Drug Supply Program of National Institute of Drug Abuse (Bethesda, MD, USA) for providing (−)-norbinaltorphimine. The authors also thank the Network and Coumputing Center, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, National Supercomputer Center of China in Guangzhou and the Computing Center of Jilin Province for the supply of computational resources. This work was supported by the National Key Research and Development Program of China (2016YFC0800907), the National Natural Science Foundation of China (21850410455, 21750110432, 21877106), the 100 Talents Program of Chinese Academy of Sciences, Young Talents Program of Chinese Academy of Agricultural Sciences, Central Public-interest Scientific Institution Basal Research Fund (NO.1610342016013), Natural Science Foundation of Jilin Province (20180101021JC), Open Fund of State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University (Grant No. KF-GN-201601), and U.S. National Institutes of Health (NIH) National Institute of Dental and Craniofacial Research Grant R01 DE017782 (to L.R.W.). The authors declare no conflicts of interest. Publisher Copyright: {\textcopyright} FASEB",

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AU - Grace, Peter M.

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AU - Kwilasz, Andrew J.

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AU - Hutchinson, Mark R.

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N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

Keywords

UN SDGs

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