Methylene Blue Is a Nonspecific Protein-Protein Interaction Inhibitor with Potential for Repurposing as an Antiviral for COVID-19.
Methylene Blue Is a Nonspecific Protein-Protein Interaction Inhibitor with Potential for Repurposing as an Antiviral for COVID-19.
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DOI：
10.3390/ph15050621
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发表时间：
2022-05-18
期刊：
影响因子：
4.6
通讯作者：
Buchwald, Peter
中科院分区：
文献类型：
--
作者：
Chuang, Sung-Ting;Papp, Henrietta;Kuczmog, Anett;Eells, Rebecca;Capcha, Jose M. Condor;Shehadeh, Lina A.;Jakab, Ferenc;Buchwald, Peter
关键词：
我们之前已经确定了亚甲蓝，一种三环吩噻嗪染料，被批准用于临床治疗高铁血红蛋白血症和其他医疗应用，作为SARS-CoV-2冠状病毒的刺突蛋白和ACE 2之间蛋白质-蛋白质相互作用（PPI）的小分子抑制剂，这是导致COVID-19大流行的冠状病毒附着和进入的第一个关键步骤。在这里，我们发现亚甲蓝浓度依赖性地抑制原始菌株以及相关变体（如D 614 G突变体和delta（B.1.617.2））的刺突蛋白的PPI，IC 50在低微摩尔范围内（1-5 μM）。亚甲蓝还显示出混杂活性，并抑制病毒蛋白的几种其他PPI（例如，HCoV-NL 63-ACE 2，丙型肝炎病毒E-CD 81）以及其他（例如，IL-2-IL-2 R α）具有相似的效力。尽管存在这种非特异性，但亚甲蓝抑制了携带SARS-CoV-2刺突蛋白的假病毒进入表达hACE 2的宿主细胞，无论是原始菌株还是δ变体。当使用病毒RNA的定量PCR分析时，它还阻断SARS-CoV-2（B.1.5）病毒在Vero E6细胞中的复制，IC 50在低微摩尔范围（1.7 μM）。因此，虽然亚甲蓝似乎是一种具有低微摩尔活性的混杂PPI抑制剂，并且具有相对较窄的治疗指数，但亚甲蓝抑制SARS-CoV-2（包括其几种突变变体）的进入和复制，并且有可能成为预防和治疗COVID-19的廉价、广谱、口服生物活性小分子抗病毒药物。
We have previously identified methylene blue, a tricyclic phenothiazine dye approved for clinical use for the treatment of methemoglobinemia and for other medical applications as a small-molecule inhibitor of the protein–protein interaction (PPI) between the spike protein of the SARS-CoV-2 coronavirus and ACE2, the first critical step of the attachment and entry of this coronavirus responsible for the COVID-19 pandemic. Here, we show that methylene blue concentration dependently inhibits this PPI for the spike protein of the original strain as well as for those of variants of concern such as the D614G mutant and delta (B.1.617.2) with IC50 in the low micromolar range (1–5 μM). Methylene blue also showed promiscuous activity and inhibited several other PPIs of viral proteins (e.g., HCoV-NL63–ACE2, hepatitis C virus E–CD81) as well as others (e.g., IL-2–IL-2Rα) with similar potency. This nonspecificity notwithstanding, methylene blue inhibited the entry of pseudoviruses bearing the spike protein of SARS-CoV-2 in hACE2-expressing host cells, both for the original strain and the delta variant. It also blocked SARS-CoV-2 (B.1.5) virus replication in Vero E6 cells with an IC50 in the low micromolar range (1.7 μM) when assayed using quantitative PCR of the viral RNA. Thus, while it seems to be a promiscuous PPI inhibitor with low micromolar activity and has a relatively narrow therapeutic index, methylene blue inhibits entry and replication of SARS-CoV-2, including several of its mutant variants, and has potential as a possible inexpensive, broad-spectrum, orally bioactive small-molecule antiviral for the prevention and treatment of COVID-19.
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影响因子：
3.9
作者：
Gendrot M;Jardot P;Delandre O;Boxberger M;Andreani J;Duflot I;Le Bideau M;Mosnier J;Fonta I;Hutter S;La Scola B;Pradines B
通讯作者：
Pradines B
亚甲蓝在体外抑制 SARS-CoV-2 的复制。
DOI：
10.1016/j.ijantimicag.2020.106202
发表时间：
2020-12
影响因子：
10.8
作者：
Gendrot M;Andreani J;Duflot I;Boxberger M;Le Bideau M;Mosnier J;Jardot P;Fonta I;Rolland C;Bogreau H;Hutter S;La Scola B;Pradines B
通讯作者：
Pradines B
影响因子：
1.4
作者：
Bawaskar HS;Bawaskar PH
通讯作者：
Bawaskar PH
影响因子：
56.9
作者：
Gadek, TR;Burdick, DJ;Bodary, SC
通讯作者：
Bodary, SC
影响因子：
3.6
作者：
Condor Capcha JM;Lambert G;Dykxhoorn DM;Salerno AG;Hare JM;Whitt MA;Pahwa S;Jayaweera DT;Shehadeh LA
通讯作者：
Shehadeh LA