Differing activities of oxysterol-binding protein (OSBP) targeting anti-viral compounds

Brett L. Roberts, Zachary C. Severance, Ryan C. Bensen, Anh T. Le-McClain, Cori A. Malinky, Evan M. Mettenbrink, Juan I. Nuñez, William J. Reddig, Earl Blewett, Anthony W.G. Burgett

Research output: Contribution to journalArticle

Abstract

Oxysterol-binding Protein (OSBP) is a human lipid-transport protein required for the cellular replication of many types of viruses, including several human pathogens. The structurally-diverse small molecule compounds OSW-1, itraconazole (ITZ), T-00127-HEV2 (THEV) and TTP-8307 (TTP) inhibit viral replication through interaction with the OSBP protein. The OSW-1 compound reduces intracellular OSBP, and the reduction of OSBP protein levels persists multiple days after the OSW-1-compound treatment is stopped. The OSW-1-induced reduction of OSBP levels inhibited Enterovirus replication prophylactically in cells. In this report, the OSBP-interacting compounds ITZ, THEV, and TTP are shown not to reduce OSBP levels in cells, unlike the OSW-1-compound, and the OSW-1 compound is determined to be the only compound capable of providing prophylactic antiviral activity in cells. Furthermore, OSW-1 and THEV inhibit the binding of 25-hydroxycholesterol (25-OHC) to OSBP indicating that these compounds bind at the conserved sterol ligand binding site. The ITZ and TTP compounds do not inhibit 25-hydroxycholesterol binding to OSBP, and therefore ITZ and TTP interact with OSBP through other, unidentified binding sites. Co-administration of the THEV compound partially blocks the cellular activity of OSW-1, including the reduction of cellular OSBP protein levels; co-administration of the ITZ and TTP compounds have minimal effect on OSW-1 cellular activity further supporting different modes of interaction with these compounds to OSBP. OSW-1, ITZ, THEV, and TTP treatment alter OSBP cellular localization and levels, but in four distinct ways. Co-administration of OSW-1 and ITZ induced OSBP cellular localization patterns with features similar to the effects of ITZ and OSW-1 treatment alone. Based on these results, OSBP is capable of interacting with multiple structural classes of antiviral small molecule compounds at different binding sites, and the different compounds have distinct effects on OSBP cellular activity.

Original languageEnglish
Article number104548
JournalAntiviral Research
Volume170
DOIs
StatePublished - 1 Oct 2019

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Protein Transport
Itraconazole
oxysterol binding protein
Binding Sites
Antiviral Agents
OSW 1
Proteins
Enterovirus
Sterols
Virus Replication
thymidine 5'-triphosphate

Cite this

Roberts, B. L., Severance, Z. C., Bensen, R. C., Le-McClain, A. T., Malinky, C. A., Mettenbrink, E. M., ... Burgett, A. W. G. (2019). Differing activities of oxysterol-binding protein (OSBP) targeting anti-viral compounds. Antiviral Research, 170, [104548]. https://doi.org/10.1016/j.antiviral.2019.104548
Roberts, Brett L. ; Severance, Zachary C. ; Bensen, Ryan C. ; Le-McClain, Anh T. ; Malinky, Cori A. ; Mettenbrink, Evan M. ; Nuñez, Juan I. ; Reddig, William J. ; Blewett, Earl ; Burgett, Anthony W.G. / Differing activities of oxysterol-binding protein (OSBP) targeting anti-viral compounds. In: Antiviral Research. 2019 ; Vol. 170.
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abstract = "Oxysterol-binding Protein (OSBP) is a human lipid-transport protein required for the cellular replication of many types of viruses, including several human pathogens. The structurally-diverse small molecule compounds OSW-1, itraconazole (ITZ), T-00127-HEV2 (THEV) and TTP-8307 (TTP) inhibit viral replication through interaction with the OSBP protein. The OSW-1 compound reduces intracellular OSBP, and the reduction of OSBP protein levels persists multiple days after the OSW-1-compound treatment is stopped. The OSW-1-induced reduction of OSBP levels inhibited Enterovirus replication prophylactically in cells. In this report, the OSBP-interacting compounds ITZ, THEV, and TTP are shown not to reduce OSBP levels in cells, unlike the OSW-1-compound, and the OSW-1 compound is determined to be the only compound capable of providing prophylactic antiviral activity in cells. Furthermore, OSW-1 and THEV inhibit the binding of 25-hydroxycholesterol (25-OHC) to OSBP indicating that these compounds bind at the conserved sterol ligand binding site. The ITZ and TTP compounds do not inhibit 25-hydroxycholesterol binding to OSBP, and therefore ITZ and TTP interact with OSBP through other, unidentified binding sites. Co-administration of the THEV compound partially blocks the cellular activity of OSW-1, including the reduction of cellular OSBP protein levels; co-administration of the ITZ and TTP compounds have minimal effect on OSW-1 cellular activity further supporting different modes of interaction with these compounds to OSBP. OSW-1, ITZ, THEV, and TTP treatment alter OSBP cellular localization and levels, but in four distinct ways. Co-administration of OSW-1 and ITZ induced OSBP cellular localization patterns with features similar to the effects of ITZ and OSW-1 treatment alone. Based on these results, OSBP is capable of interacting with multiple structural classes of antiviral small molecule compounds at different binding sites, and the different compounds have distinct effects on OSBP cellular activity.",
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Roberts, BL, Severance, ZC, Bensen, RC, Le-McClain, AT, Malinky, CA, Mettenbrink, EM, Nuñez, JI, Reddig, WJ, Blewett, E & Burgett, AWG 2019, 'Differing activities of oxysterol-binding protein (OSBP) targeting anti-viral compounds', Antiviral Research, vol. 170, 104548. https://doi.org/10.1016/j.antiviral.2019.104548

Differing activities of oxysterol-binding protein (OSBP) targeting anti-viral compounds. / Roberts, Brett L.; Severance, Zachary C.; Bensen, Ryan C.; Le-McClain, Anh T.; Malinky, Cori A.; Mettenbrink, Evan M.; Nuñez, Juan I.; Reddig, William J.; Blewett, Earl; Burgett, Anthony W.G.

In: Antiviral Research, Vol. 170, 104548, 01.10.2019.

Research output: Contribution to journalArticle

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T1 - Differing activities of oxysterol-binding protein (OSBP) targeting anti-viral compounds

AU - Roberts, Brett L.

AU - Severance, Zachary C.

AU - Bensen, Ryan C.

AU - Le-McClain, Anh T.

AU - Malinky, Cori A.

AU - Mettenbrink, Evan M.

AU - Nuñez, Juan I.

AU - Reddig, William J.

AU - Blewett, Earl

AU - Burgett, Anthony W.G.

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N2 - Oxysterol-binding Protein (OSBP) is a human lipid-transport protein required for the cellular replication of many types of viruses, including several human pathogens. The structurally-diverse small molecule compounds OSW-1, itraconazole (ITZ), T-00127-HEV2 (THEV) and TTP-8307 (TTP) inhibit viral replication through interaction with the OSBP protein. The OSW-1 compound reduces intracellular OSBP, and the reduction of OSBP protein levels persists multiple days after the OSW-1-compound treatment is stopped. The OSW-1-induced reduction of OSBP levels inhibited Enterovirus replication prophylactically in cells. In this report, the OSBP-interacting compounds ITZ, THEV, and TTP are shown not to reduce OSBP levels in cells, unlike the OSW-1-compound, and the OSW-1 compound is determined to be the only compound capable of providing prophylactic antiviral activity in cells. Furthermore, OSW-1 and THEV inhibit the binding of 25-hydroxycholesterol (25-OHC) to OSBP indicating that these compounds bind at the conserved sterol ligand binding site. The ITZ and TTP compounds do not inhibit 25-hydroxycholesterol binding to OSBP, and therefore ITZ and TTP interact with OSBP through other, unidentified binding sites. Co-administration of the THEV compound partially blocks the cellular activity of OSW-1, including the reduction of cellular OSBP protein levels; co-administration of the ITZ and TTP compounds have minimal effect on OSW-1 cellular activity further supporting different modes of interaction with these compounds to OSBP. OSW-1, ITZ, THEV, and TTP treatment alter OSBP cellular localization and levels, but in four distinct ways. Co-administration of OSW-1 and ITZ induced OSBP cellular localization patterns with features similar to the effects of ITZ and OSW-1 treatment alone. Based on these results, OSBP is capable of interacting with multiple structural classes of antiviral small molecule compounds at different binding sites, and the different compounds have distinct effects on OSBP cellular activity.

AB - Oxysterol-binding Protein (OSBP) is a human lipid-transport protein required for the cellular replication of many types of viruses, including several human pathogens. The structurally-diverse small molecule compounds OSW-1, itraconazole (ITZ), T-00127-HEV2 (THEV) and TTP-8307 (TTP) inhibit viral replication through interaction with the OSBP protein. The OSW-1 compound reduces intracellular OSBP, and the reduction of OSBP protein levels persists multiple days after the OSW-1-compound treatment is stopped. The OSW-1-induced reduction of OSBP levels inhibited Enterovirus replication prophylactically in cells. In this report, the OSBP-interacting compounds ITZ, THEV, and TTP are shown not to reduce OSBP levels in cells, unlike the OSW-1-compound, and the OSW-1 compound is determined to be the only compound capable of providing prophylactic antiviral activity in cells. Furthermore, OSW-1 and THEV inhibit the binding of 25-hydroxycholesterol (25-OHC) to OSBP indicating that these compounds bind at the conserved sterol ligand binding site. The ITZ and TTP compounds do not inhibit 25-hydroxycholesterol binding to OSBP, and therefore ITZ and TTP interact with OSBP through other, unidentified binding sites. Co-administration of the THEV compound partially blocks the cellular activity of OSW-1, including the reduction of cellular OSBP protein levels; co-administration of the ITZ and TTP compounds have minimal effect on OSW-1 cellular activity further supporting different modes of interaction with these compounds to OSBP. OSW-1, ITZ, THEV, and TTP treatment alter OSBP cellular localization and levels, but in four distinct ways. Co-administration of OSW-1 and ITZ induced OSBP cellular localization patterns with features similar to the effects of ITZ and OSW-1 treatment alone. Based on these results, OSBP is capable of interacting with multiple structural classes of antiviral small molecule compounds at different binding sites, and the different compounds have distinct effects on OSBP cellular activity.

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Roberts BL, Severance ZC, Bensen RC, Le-McClain AT, Malinky CA, Mettenbrink EM et al. Differing activities of oxysterol-binding protein (OSBP) targeting anti-viral compounds. Antiviral Research. 2019 Oct 1;170. 104548. https://doi.org/10.1016/j.antiviral.2019.104548