Synthesis and Cell-Based Evaluation of Umifenovir Analogues as Anti-SARS-CoV-2 Agents

IF 1.5 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY
Hiroaki Tanaka, Seiya Miyagi, Tomoko Morita, Hiroaki Ishii, Natsuki Mori, Kaho Oishi, Takemasa Sakaguchi, Toyonobu Usuki
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Abstract

Umifenovir is a broad-spectrum antiviral agent used to treat influenza in China and Russia, and it has been studied as an antiviral agent for the treatment of coronavirus disease 2019 (COVID-19). We have previously reported the synthesis of novel umifenovir analogues and their biological evaluation with a focus on their inhibitory activity against the binding of the spike glycoprotein (S-protein) of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the angiotensin-converting enzyme 2 (ACE2) receptor; however, no strong inhibitory activity was observed from these analogues. In the present study, an additional set of umifenovir analogues was synthesized with replacement of the substituents at the 2-, 3-, and 4-positions of the indole, and a cell-based assay using SARS-CoV-2 (B.1.1) was performed to examine the antiviral activity of the analogues. We found that one of the newly synthesized umifenovir analogues exhibited antiviral activity and reduced the viral load to 0.06 % as compared to the control when it was assessed in the presence of nafamostat and marimastat, which inhibit cell-surface viral entry. In contrast, when this analogue was evaluated without the addition of nafamostat or marimastat, it exhibited less antiviral activity, suggesting that the umifenovir analogue would exert antiviral activity mainly by inhibiting endosome-mediated viral entry.

Abstract Image

作为抗 SARS-CoV-2 药物的 Umifenovir 类似物的合成和基于细胞的评估
乌米诺韦是一种广谱抗病毒药物,在中国和俄罗斯被用于治疗流感,它还被研究用作治疗2019年冠状病毒病(COVID-19)的抗病毒药物。我们以前曾报道过新型乌米诺韦类似物的合成及其生物学评价,重点是它们对严重急性呼吸系统综合征冠状病毒-2(SARS-CoV-2)的尖峰糖蛋白(S蛋白)和血管紧张素转换酶 2(ACE2)受体结合的抑制活性;然而,这些类似物没有观察到很强的抑制活性。在本研究中,我们通过替换吲哚 2-、3-和 4-位上的取代基合成了另外一组乌米诺韦类似物,并使用 SARS-CoV-2 (B.1.1) 进行了基于细胞的检测,以检验这些类似物的抗病毒活性。我们发现,新合成的一种乌米诺韦类似物具有抗病毒活性,在抑制细胞表面病毒进入的纳伐司他和马立司他(marimastat)存在的情况下,与对照组相比,病毒载量降低到了 0.06%。相反,在不添加萘莫司他或马立司他(marimastat)的情况下评估该类似物时,其抗病毒活性较低,这表明乌米诺韦类似物主要通过抑制内膜介导的病毒进入来发挥抗病毒活性。
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来源期刊
Helvetica Chimica Acta
Helvetica Chimica Acta 化学-化学综合
CiteScore
3.00
自引率
0.00%
发文量
60
审稿时长
2.3 months
期刊介绍: Helvetica Chimica Acta, founded by the Swiss Chemical Society in 1917, is a monthly multidisciplinary journal dedicated to the dissemination of knowledge in all disciplines of chemistry (organic, inorganic, physical, technical, theoretical and analytical chemistry) as well as research at the interface with other sciences, where molecular aspects are key to the findings. Helvetica Chimica Acta is committed to the publication of original, high quality papers at the frontier of scientific research. All contributions will be peer reviewed with the highest possible standards and published within 3 months of receipt, with no restriction on the length of the papers and in full color.
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