Discovery of Triple Inhibitors of Both SARS-CoV-2 Proteases and Human Cathepsin L.
Discovery of Triple Inhibitors of Both SARS-CoV-2 Proteases and Human Cathepsin L.
复制标题
DOI：
10.3390/ph15060744
复制
发表时间：
2022-06-13
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
一种SARS-CoV-2主要蛋白酶的抑制剂最近已被FDA批准，但它仅针对SARS-CoV-2主要蛋白酶（Mpro）。在这里，我们发现了含有二硫化秋兰姆或二硫代双-（硫代甲酸酯）的抑制剂，用于对抗参与SARS-CoV-2复制的三种关键蛋白酶，包括Mpro、SARS-CoV-2木瓜蛋白酶样蛋白酶（PLpro）和人组织蛋白酶L。二硫化秋兰姆和二硫代双（硫代甲酸酯）共价抑制剂弹头的使用受到了一个想法的启发，即找到一种比双硫仑更好的替代品，双硫仑是一种获批的慢性酒精中毒治疗药物，目前正在进行针对SARS-CoV-2的2期临床试验。我们的目标是找到更有效的抑制剂，靶向病毒蛋白酶和一种必需的人类蛋白酶，以减少剂量，提高疗效，并尽量减少与这些药物相关的不良反应。我们发现，在针对SARS-CoV-2 Mpro、SARS-CoV-2 PLpro和人组织蛋白酶L的酶促测定中，编码为RI 175、RI 173和RI 172的化合物是最有效的抑制剂，IC 50为300、200和200 nM，分别比双硫仑有效约5倍、19倍和11倍。此外，RI 173在基于细胞的毒性试验中针对SARS-CoV-2进行了测试，并显示出比双硫仑具有更大的抗病毒作用。所鉴定的化合物证明了二硫化秋兰姆或二硫代双-（硫代甲酸酯）作为小分子中的反应性官能团的有希望的潜力，可以进一步开发用于治疗COVID-19病毒或相关变体。
One inhibitor of the main SARS-CoV-2 protease has been approved recently by the FDA, yet it targets only SARS-CoV-2 main protease (Mpro). Here, we discovered inhibitors containing thiuram disulfide or dithiobis-(thioformate) tested against three key proteases involved in SARS-CoV-2 replication, including Mpro, SARS-CoV-2 papain-like protease (PLpro), and human cathepsin L. The use of thiuram disulfide and dithiobis-(thioformate) covalent inhibitor warheads was inspired by an idea to find a better alternative than disulfiram, an approved treatment for chronic alcoholism that is currently in phase 2 clinical trials against SARS-CoV-2. Our goal was to find more potent inhibitors that target both viral proteases and one essential human protease to reduce the dosage, improve the efficacy, and minimize the adverse effects associated with these agents. We found that compounds coded as RI175, RI173, and RI172 were the most potent inhibitors in an enzymatic assay against SARS-CoV-2 Mpro, SARS-CoV-2 PLpro, and human cathepsin L, with IC50s of 300, 200, and 200 nM, which is about 5-, 19-, and 11-fold more potent than disulfiram, respectively. In addition, RI173 was tested against SARS-CoV-2 in a cell-based and toxicity assay and was shown to have a greater antiviral effect than disulfiram. The identified compounds demonstrated the promising potential of thiuram disulfide or dithiobis-(thioformate) as a reactive functional group in small molecules that could be further developed for treatment of the COVID-19 virus or related variants.
登录
查看更多内容
影响因子：
7.3
作者：
Brahemi G;Kona FR;Fiasella A;Buac D;Soukupová J;Brancale A;Burger AM;Westwell AD
通讯作者：
Westwell AD
影响因子：
28.3
作者：
Gorbalenya, Alexander E.;Baker, Susan C.;Ziebuhr, John
通讯作者：
Ziebuhr, John
影响因子：
18.2
作者：
Ma C;Sacco MD;Xia Z;Lambrinidis G;Townsend JA;Hu Y;Meng X;Szeto T;Ba M;Zhang X;Gongora M;Zhang F;Marty MT;Xiang Y;Kolocouris A;Chen Y;Wang J
通讯作者：
Wang J
影响因子：
56.9
作者：
Dai, Wenhao;Zhang, Bing;Liu, Hong
通讯作者：
Liu, Hong
影响因子：
4.6
作者：
Bolcato G;Bissaro M;Pavan M;Sturlese M;Moro S
通讯作者：
Moro S