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Published on: October 29, 2015
Transient Compound Treatment Induces a Multigenerational Reduction of Oxysterol-Binding Protein (OSBP) Levels and
Brett L Roberts1, Zachary C Severance1, Ryan C Bensen1
1Department of Chemistry and Biochemistry , The University of Oklahoma , 101 Stephenson Parkway , Norman , Oklahoma 73019 , United States.
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.
Insights
A novel compound, OSW-1, dramatically reduces oxysterol-binding protein (OSBP) levels in cells, offering a new strategy for broad-spectrum antiviral therapies against enteroviruses.
Area of Science:
- Biochemistry
- Virology
- Cell Biology
Background:
- Oxysterol-binding protein (OSBP) is crucial for the replication of enteroviruses, a group of significant human pathogens.
- Targeting host factors like OSBP presents a promising strategy for developing broad-spectrum antiviral treatments.
Purpose of the Study:
- To investigate the effects of the natural product compound OSW-1 on cellular OSBP levels.
- To explore the potential of OSW-1 as an antiviral agent against enteroviruses by targeting OSBP.
Main Methods:
- Treatment of various cell lines with low-dose OSW-1 for short durations.
- Analysis of OSBP levels, cytotoxicity, cellular proliferation, and proteome.
- Investigation of the persistence and inheritance of OSBP reduction across cell generations.
- Exploration of underlying mechanisms including proteasomal degradation, mRNA levels, and autophagy.
Main Results:
- Short-term, low-dose OSW-1 treatment reduced cellular OSBP levels by ~90% without cytotoxicity or global proteome changes.
- The OSBP reduction persisted for multiple days and across cell generations, even after OSW-1 was undetectable.
- The mechanism did not involve proteasomal degradation or reduced OSBP mRNA, though transient autophagy was observed.
- Reduced OSBP levels significantly inhibited enterovirus replication.
Conclusions:
- OSW-1 treatment triggers a stable, inheritable OSBP reduction, indicating a novel host-specific regulatory process.
- This OSBP-targeting approach offers a new avenue for broad-spectrum anti-enterovirus activity.
- OSW-1 represents a potential prophylactic antiviral treatment by targeting a human host protein.
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