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.

中文翻译：

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瞬态化合物处理可诱导多代减少氧固醇结合蛋白（OSBP）的水平和预防性抗病毒活性。

氧固醇结合蛋白（OSBP）是复制肠道病毒属病毒（包括许多重要的人类病原体）所需的脂质运输和调节蛋白。低剂量（即1 nM）天然产物化合物OSW-1的短期暴露（即1-6小时）可在多种可测量的细胞系中诱导细胞OSBP降低约90％，且无可测的细胞毒性，细胞增殖缺陷或整体蛋白质组减少。有趣的是，低剂量，短暂的OSW-1化合物治疗结束且细胞内OSW-1化合物水平降至不可检测的水平后，OSBP水平的降低持续数天。OSBP-1化合物治疗停止后，在多代细胞中遗传了OSBP水平的降低。持续多日 由OSW-1化合物触发的OSBP水平的多代降低不是由于OSBP的蛋白酶体降解或由于OSBP mRNA水平的降低。OSW-1化合物处理可诱导细胞发生瞬时自噬，但阻断自噬不能拯救OSBP水平。尽管尚未确定长期OSBP抑制的特定细胞机制，但这些结果清楚地表明了OSBP特异性细胞调节过程的存在，该过程在用OSBP结合化合物治疗后触发。短期，短暂OSW-1化合物治疗后OSBP水平的稳定降低将成为了解OSBP调节和细胞功能的有力工具。另外，由瞬时OSW-1化合物处理触发的OSBP水平的持续降低大大减少了在处理过的细胞中的病毒复制。