Differing activities of oxysterol-binding protein (OSBP) targeting anti-viral compounds.
Differing activities of oxysterol-binding protein (OSBP) targeting anti-viral compounds.
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DOI：
10.1016/j.antiviral.2019.104548
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发表时间：
2019-07
影响因子：
7.6
通讯作者：
B. L. Roberts;Zachary C Severance;Ryan C. Bensen;Anh T. Le;Cori A Malinky;Evan M Mettenbrink;J. Núñez;William J Reddig;E. Blewett;Anthony W. G. Burgett
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文献类型：
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作者：
B. L. Roberts;Zachary C Severance;Ryan C. Bensen;Anh T. Le;Cori A Malinky;Evan M Mettenbrink;J. Núñez;William J Reddig;E. Blewett;Anthony W. G. Burgett
氧甾醇结合蛋白（OSBP）是一种人体脂质转运蛋白，是多种病毒（包括几种人类病原体）的细胞复制所必需的。结构多样的小分子化合物OSW-1、伊曲康唑（ITZ）、T-00127-HEV2 （THEV）和TTP-8307 （TTP）通过与OSBP蛋白相互作用抑制病毒复制。OSW-1化合物降低细胞内OSBP，并且OSBP蛋白水平的降低在OSW-1化合物治疗停止后持续数天。osw -1诱导的OSBP水平降低可预防性地抑制肠道病毒在细胞中的复制。在本报告中，与OSW-1化合物不同，OSW-1化合物与OSW-1相互作用的化合物ITZ、THEV和TTP显示不会降低细胞中的OSBP水平，并且OSW-1化合物被确定为唯一能够在细胞中提供预防性抗病毒活性的化合物。此外，OSW-1和THEV抑制25-羟基胆固醇（25-OHC）与OSBP的结合，表明这些化合物结合在保守的甾醇配体结合位点。ITZ和TTP化合物不抑制25-羟基胆固醇与OSBP的结合，因此ITZ和TTP通过其他未知的结合位点与OSBP相互作用。共给药THEV化合物部分阻断OSW-1的细胞活性，包括降低细胞OSBP蛋白水平；同时施用ITZ和TTP化合物对OSW-1细胞活性的影响最小，进一步支持与这些化合物相互作用的不同模式对OSBP的影响。OSW-1、ITZ、THEV和TTP治疗改变OSBP细胞定位和水平，但有四种不同的方式。同时给药OSW-1和ITZ诱导OSBP细胞定位模式，其特征与单独给药OSW-1的作用相似。基于这些结果，OSBP能够在不同的结合位点与多种结构类抗病毒小分子化合物相互作用，并且不同的化合物对OSBP的细胞活性有不同的影响。
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.