The essential role of SMAR1 in HIV-1 transcription and LTR driven gene expression suggests SMAR1 as an HIV dependency factor (HDF) and a potential anti-HIV therapeutic target. Here, we report for the first time, anti-HIV activity of 8 novel isothiocyanate (ITC) derivatives that differentially stabilise SMAR1. Out of 8 novel ITC derivatives, SCS-OCL-381 was observed to inhibit HIV-1 replication most significantly at the noncytotoxic concentration in reporter T-cell line, CEM-GFP. Further, the highly conserved anti-HIV activity of SCS-OCL-381 is a cell type, virus isolate and viral load independent phenomena and is approximately 3 fold more effective than the representative ITC, Sulforaphane (SFN). Further, SCS-OCL-381 does not hamper the activity of viral enzymes reverse transcriptase, integrase and protease. Mechanistically, SCS-OCL-381 stabilises SMAR1 which, otherwise undergoes proteasomal degradation upon HIV-1 infection in T-cells. This stabilisation results in the recruitment of repressor complex on HIV-1 LTR resulting in repression of LTR mediated transcription and gene expression. These inhibitory consequences were further confirmed by reporter based LTR activity assays in different cell lines. Taken together, these findings highlight the anti-HIV potential of novel ITC derivatives by the stabilisation of SMAR1 and strongly support further in vivo characterisation and potential translational applications of SCS-OCL-381.

中文翻译：

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一种新型的异硫氰酸酯衍生物通过调节核基质相关蛋白SMAR1抑制HIV-1基因的表达和复制。

SMAR1在HIV-1转录和LTR驱动的基因表达中的重要作用表明SMAR1作为HIV依赖因子（HDF）和潜在的抗HIV治疗靶标。在这里，我们首次报告，差异稳定SMAR1的8个新型异硫氰酸酯（ITC）衍生物的抗HIV活性。在8种新型ITC衍生物中，观察到SCS-OCL-381在报告T细胞系CEM-GFP的非细胞毒性浓度下最能抑制HIV-1复制。此外，SCS-OCL-381的高度保守的抗HIV活性是细胞类型，病毒分离株和病毒载量独立现象，并且比代表性的ITC萝卜硫素（SFN）效力高约3倍。此外，SCS-OCL-381不妨碍病毒酶逆转录酶，整合酶和蛋白酶的活性。机械上，SCS-OCL-381可稳定SMAR1，否则SMAR1在T细胞中感染HIV-1后会发生蛋白酶体降解。这种稳定作用导致HIV-1 LTR上阻遏物复合物的募集，导致LTR介导的转录和基因表达受到抑制。通过在不同细胞系中基于报告基因的LTR活性测定进一步证实了这些抑制作用。综上所述，这些发现通过稳定SMAR1突出了新型ITC衍生物的抗HIV潜力，并强烈支持SCS-OCL-381的进一步体内表征和潜在翻译应用。通过在不同细胞系中基于报告基因的LTR活性测定进一步证实了这些抑制作用。综上所述，这些发现通过稳定SMAR1突出了新型ITC衍生物的抗HIV潜力，并强烈支持SCS-OCL-381的进一步体内表征和潜在翻译应用。通过在不同细胞系中基于报告基因的LTR活性测定进一步证实了这些抑制作用。综上所述，这些发现通过稳定SMAR1突出了新型ITC衍生物的抗HIV潜力，并强烈支持SCS-OCL-381的进一步体内表征和潜在翻译应用。