The Thiazole-5-Carboxamide GPS491 Inhibits HIV-1, Adenovirus, and Coronavirus Replication by Altering RNA Processing/Accumulation.
The Thiazole-5-Carboxamide GPS491 Inhibits HIV-1, Adenovirus, and Coronavirus Replication by Altering RNA Processing/Accumulation.
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DOI：
10.3390/v14010060
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发表时间：
2021-12-30
期刊：
影响因子：
--
通讯作者：
Cochrane A
中科院分区：
文献类型：
--
作者：
Dahal S;Cheng R;Cheung PK;Been T;Malty R;Geng M;Manianis S;Shkreta L;Jahanshahi S;Toutant J;Chan R;Park S;Brockman MA;Babu M;Mubareka S;Mossman K;Banerjee A;Gray-Owen S;Brown M;Houry WA;Chabot B;Grierson D;Cochrane A
对先前描述的艾滋病毒-1的二苯乙烯类抑制剂5350150(2-(2-(5-硝基-2-噻吩基)乙烯基)喹啉)进行了药物化学优化，从而鉴定了噻唑-5-甲酰胺衍生物(GPS491)，该化合物具有较强的抗艾滋病毒-1活性，且毒性较低。在这份报告中，我们证明了GPS491阻断HIV-1复制伴随着病毒基因表达的急剧抑制(IC50~0.25µM)，以及非剪接、单剪接和多剪接HIV-1 RNA的产生的变化。GPS491对腺病毒和多冠状病毒的复制也有抑制作用。低µM剂量的GPS491可使腺病毒感染产量减少约1000倍，改变病毒早期基因表达/病毒E1a RNA加工，阻断病毒DNA扩增，并抑制晚期(六邻体)基因表达。多个冠状病毒(229E、OC43、SARS-CoV2)在加入GPS491后复制丧失，与病毒结构蛋白表达和病毒颗粒形成的抑制有关。与观察到的病毒RNA加工的变化一致，GPS491处理诱导了剪接调节SR蛋白的积累/磷酸化/功能的选择性改变。我们的研究证实，一种影响参与RNA加工的细胞因子活性的化合物可以防止几种病毒的复制，而对细胞活力的影响最小。
Medicinal chemistry optimization of a previously described stilbene inhibitor of HIV-1, 5350150 (2-(2-(5-nitro-2-thienyl)vinyl)quinoline), led to the identification of the thiazole-5-carboxamide derivative (GPS491), which retained potent anti-HIV-1 activity with reduced toxicity. In this report, we demonstrate that the block of HIV-1 replication by GPS491 is accompanied by a drastic inhibition of viral gene expression (IC50 ~ 0.25 µM), and alterations in the production of unspliced, singly spliced, and multiply spliced HIV-1 RNAs. GPS491 also inhibited the replication of adenovirus and multiple coronaviruses. Low µM doses of GPS491 reduced adenovirus infectious yield ~1000 fold, altered virus early gene expression/viral E1A RNA processing, blocked viral DNA amplification, and inhibited late (hexon) gene expression. Loss of replication of multiple coronaviruses (229E, OC43, SARS-CoV2) upon GPS491 addition was associated with the inhibition of viral structural protein expression and the formation of virus particles. Consistent with the observed changes in viral RNA processing, GPS491 treatment induced selective alterations in the accumulation/phosphorylation/function of splicing regulatory SR proteins. Our study establishes that a compound that impacts the activity of cellular factors involved in RNA processing can prevent the replication of several viruses with minimal effect on cell viability.
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