Transient Compound Treatment Induces a Multigenerational Reduction of Oxysterol-Binding Protein (OSBP) Levels and Prophylactic Antiviral Activity

Brett L. Roberts, Zachary C. Severance, Ryan C. Bensen, Anh T. Le, Naga Rama Kothapalli, Juan I. Nuñez, Hongyan Ma, Si Wu, Shawna J. Standke, Zhibo Yang, William J. Reddig, Earl L. Blewett, Anthony W.G. Burgett

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Oxysterol-binding protein (OSBP) is a lipid transport and regulatory protein required for the replication of Enterovirus genus viruses, which includes many significant human pathogens. Short-term exposure (i.e., 1-6 h) to a low dose (i.e., 1 nM) of the natural product compound OSW-1 induces a reduction of cellular OSBP levels by ∼90% in multiple different cell lines with no measurable cytotoxicity, defect in cellular proliferation, or global proteome reduction. Interestingly, the reduction of OSBP levels persists multiple days after the low-dose, transient OSW-1 compound treatment is ended and the intracellular OSW-1 compound levels drop to undetectable levels. The reduction in OSBP levels is inherited in multiple generations of cells that are propagated after the OSW-1 compound treatment is stopped. The enduring multiday, multigenerational reduction of OSBP levels triggered by the OSW-1 compound is not due to proteasome degradation of OSBP or due to a reduction in OSBP mRNA levels. OSW-1 compound treatment induces transient autophagy in cells, but blocking autophagy does not rescue OSBP levels. Although the specific cellular mechanism of long-term OSBP repression is not yet identified, these results clearly show the existence of an OSBP specific cellular regulation process that is triggered upon treatment with an OSBP-binding compound. The stable reduction of OSBP levels upon short-term, transient OSW-1 compound treatment will be a powerful tool to understand OSBP regulation and cellular function. Additionally, the persistent reduction in OSBP levels triggered by the transient OSW-1 compound treatment substantially reduces viral replication in treated cells. Therefore, the long-term, compound-induced reduction of OSBP in cells presents a new route to broad spectrum anti-Enterovirus activity, including as a novel route to antiviral prophylactic treatment through small molecule targeting a human host protein.

Original languageEnglish
JournalACS Chemical Biology
DOIs
StateAccepted/In press - 1 Jan 2019

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Antiviral Agents
Enterovirus
Autophagy
oxysterol binding protein
Cells
OSW 1
Pathogens
Proteasome Endopeptidase Complex
Proteome
Cytotoxicity
Biological Products
Viruses
Protein Binding
Carrier Proteins
Proteins
Cell Proliferation

Cite this

Roberts, B. L., Severance, Z. C., Bensen, R. C., Le, A. T., Kothapalli, N. R., Nuñez, J. I., ... Burgett, A. W. G. (Accepted/In press). Transient Compound Treatment Induces a Multigenerational Reduction of Oxysterol-Binding Protein (OSBP) Levels and Prophylactic Antiviral Activity. ACS Chemical Biology. https://doi.org/10.1021/acschembio.8b00984
Roberts, Brett L. ; Severance, Zachary C. ; Bensen, Ryan C. ; Le, Anh T. ; Kothapalli, Naga Rama ; Nuñez, Juan I. ; Ma, Hongyan ; Wu, Si ; Standke, Shawna J. ; Yang, Zhibo ; Reddig, William J. ; Blewett, Earl L. ; Burgett, Anthony W.G. / Transient Compound Treatment Induces a Multigenerational Reduction of Oxysterol-Binding Protein (OSBP) Levels and Prophylactic Antiviral Activity. In: ACS Chemical Biology. 2019.
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abstract = "Oxysterol-binding protein (OSBP) is a lipid transport and regulatory protein required for the replication of Enterovirus genus viruses, which includes many significant human pathogens. Short-term exposure (i.e., 1-6 h) to a low dose (i.e., 1 nM) of the natural product compound OSW-1 induces a reduction of cellular OSBP levels by ∼90{\%} in multiple different cell lines with no measurable cytotoxicity, defect in cellular proliferation, or global proteome reduction. Interestingly, the reduction of OSBP levels persists multiple days after the low-dose, transient OSW-1 compound treatment is ended and the intracellular OSW-1 compound levels drop to undetectable levels. The reduction in OSBP levels is inherited in multiple generations of cells that are propagated after the OSW-1 compound treatment is stopped. The enduring multiday, multigenerational reduction of OSBP levels triggered by the OSW-1 compound is not due to proteasome degradation of OSBP or due to a reduction in OSBP mRNA levels. OSW-1 compound treatment induces transient autophagy in cells, but blocking autophagy does not rescue OSBP levels. Although the specific cellular mechanism of long-term OSBP repression is not yet identified, these results clearly show the existence of an OSBP specific cellular regulation process that is triggered upon treatment with an OSBP-binding compound. The stable reduction of OSBP levels upon short-term, transient OSW-1 compound treatment will be a powerful tool to understand OSBP regulation and cellular function. Additionally, the persistent reduction in OSBP levels triggered by the transient OSW-1 compound treatment substantially reduces viral replication in treated cells. Therefore, the long-term, compound-induced reduction of OSBP in cells presents a new route to broad spectrum anti-Enterovirus activity, including as a novel route to antiviral prophylactic treatment through small molecule targeting a human host protein.",
author = "Roberts, {Brett L.} and Severance, {Zachary C.} and Bensen, {Ryan C.} and Le, {Anh T.} and Kothapalli, {Naga Rama} and Nu{\~n}ez, {Juan I.} and Hongyan Ma and Si Wu and Standke, {Shawna J.} and Zhibo Yang and Reddig, {William J.} and Blewett, {Earl L.} and Burgett, {Anthony W.G.}",
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Roberts, BL, Severance, ZC, Bensen, RC, Le, AT, Kothapalli, NR, Nuñez, JI, Ma, H, Wu, S, Standke, SJ, Yang, Z, Reddig, WJ, Blewett, EL & Burgett, AWG 2019, 'Transient Compound Treatment Induces a Multigenerational Reduction of Oxysterol-Binding Protein (OSBP) Levels and Prophylactic Antiviral Activity', ACS Chemical Biology. https://doi.org/10.1021/acschembio.8b00984

Transient Compound Treatment Induces a Multigenerational Reduction of Oxysterol-Binding Protein (OSBP) Levels and Prophylactic Antiviral Activity. / Roberts, Brett L.; Severance, Zachary C.; Bensen, Ryan C.; Le, Anh T.; Kothapalli, Naga Rama; Nuñez, Juan I.; Ma, Hongyan; Wu, Si; Standke, Shawna J.; Yang, Zhibo; Reddig, William J.; Blewett, Earl L.; Burgett, Anthony W.G.

In: ACS Chemical Biology, 01.01.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Transient Compound Treatment Induces a Multigenerational Reduction of Oxysterol-Binding Protein (OSBP) Levels and Prophylactic Antiviral Activity

AU - Roberts, Brett L.

AU - Severance, Zachary C.

AU - Bensen, Ryan C.

AU - Le, Anh T.

AU - Kothapalli, Naga Rama

AU - Nuñez, Juan I.

AU - Ma, Hongyan

AU - Wu, Si

AU - Standke, Shawna J.

AU - Yang, Zhibo

AU - Reddig, William J.

AU - Blewett, Earl L.

AU - Burgett, Anthony W.G.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Oxysterol-binding protein (OSBP) is a lipid transport and regulatory protein required for the replication of Enterovirus genus viruses, which includes many significant human pathogens. Short-term exposure (i.e., 1-6 h) to a low dose (i.e., 1 nM) of the natural product compound OSW-1 induces a reduction of cellular OSBP levels by ∼90% in multiple different cell lines with no measurable cytotoxicity, defect in cellular proliferation, or global proteome reduction. Interestingly, the reduction of OSBP levels persists multiple days after the low-dose, transient OSW-1 compound treatment is ended and the intracellular OSW-1 compound levels drop to undetectable levels. The reduction in OSBP levels is inherited in multiple generations of cells that are propagated after the OSW-1 compound treatment is stopped. The enduring multiday, multigenerational reduction of OSBP levels triggered by the OSW-1 compound is not due to proteasome degradation of OSBP or due to a reduction in OSBP mRNA levels. OSW-1 compound treatment induces transient autophagy in cells, but blocking autophagy does not rescue OSBP levels. Although the specific cellular mechanism of long-term OSBP repression is not yet identified, these results clearly show the existence of an OSBP specific cellular regulation process that is triggered upon treatment with an OSBP-binding compound. The stable reduction of OSBP levels upon short-term, transient OSW-1 compound treatment will be a powerful tool to understand OSBP regulation and cellular function. Additionally, the persistent reduction in OSBP levels triggered by the transient OSW-1 compound treatment substantially reduces viral replication in treated cells. Therefore, the long-term, compound-induced reduction of OSBP in cells presents a new route to broad spectrum anti-Enterovirus activity, including as a novel route to antiviral prophylactic treatment through small molecule targeting a human host protein.

AB - Oxysterol-binding protein (OSBP) is a lipid transport and regulatory protein required for the replication of Enterovirus genus viruses, which includes many significant human pathogens. Short-term exposure (i.e., 1-6 h) to a low dose (i.e., 1 nM) of the natural product compound OSW-1 induces a reduction of cellular OSBP levels by ∼90% in multiple different cell lines with no measurable cytotoxicity, defect in cellular proliferation, or global proteome reduction. Interestingly, the reduction of OSBP levels persists multiple days after the low-dose, transient OSW-1 compound treatment is ended and the intracellular OSW-1 compound levels drop to undetectable levels. The reduction in OSBP levels is inherited in multiple generations of cells that are propagated after the OSW-1 compound treatment is stopped. The enduring multiday, multigenerational reduction of OSBP levels triggered by the OSW-1 compound is not due to proteasome degradation of OSBP or due to a reduction in OSBP mRNA levels. OSW-1 compound treatment induces transient autophagy in cells, but blocking autophagy does not rescue OSBP levels. Although the specific cellular mechanism of long-term OSBP repression is not yet identified, these results clearly show the existence of an OSBP specific cellular regulation process that is triggered upon treatment with an OSBP-binding compound. The stable reduction of OSBP levels upon short-term, transient OSW-1 compound treatment will be a powerful tool to understand OSBP regulation and cellular function. Additionally, the persistent reduction in OSBP levels triggered by the transient OSW-1 compound treatment substantially reduces viral replication in treated cells. Therefore, the long-term, compound-induced reduction of OSBP in cells presents a new route to broad spectrum anti-Enterovirus activity, including as a novel route to antiviral prophylactic treatment through small molecule targeting a human host protein.

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