{"title":"从睡茄（Withania somnifera）中提取的甾族内酯能有效针对 SARS-CoV-2 的 Beta、Gamma、Delta 和 Omicron 变体，并显示出对病毒感染和延续的易感性降低：一种多药理学方法。","authors":"Aditi Srivastava, Rumana Ahmad, Irshad A Wani, Sahabjada Siddiqui, Kusum Yadav, Anchal Trivedi, Shivbrat Upadhyay, Ishrat Husain, Tanveer Ahamad, Shivanand S Dudhagi","doi":"10.1007/s40203-023-00184-y","DOIUrl":null,"url":null,"abstract":"<p><p>Prevention from disease is presently the cornerstone of the fight against COVID-19. With the rapid emergence of novel SARS-CoV-2 variants, there is an urgent need for novel or repurposed agents to strengthen and fortify the immune system. Existing vaccines induce several systemic and local side-effects that can lead to severe consequences. Moreover, elevated cytokines in COVID-19 patients with cancer as co-morbidity represent a significant bottleneck in disease prognosis and therapy. <i>Withania somnifera</i> (WS) and its phytoconstituent(s) have immense untapped immunomodulatory and therapeutic potential and the anticancer potential of WS is well documented. To this effect, WS methanolic extract (WSME) was characterized using HPLC. Withanolides were identified as the major phytoconstituents. In vitro cytotoxicity of WSME was determined against human breast MDA-MB-231 and normal Vero cells using MTT assay. WSME displayed potent cytotoxicity against MDA-MB-231 cells (IC<sub>50</sub>: 66 µg/mL) and no effect on Vero cells in the above range. MD simulations of Withanolide A with SARS-CoV-2 main protease and spike receptor-binding domain as well as Withanolide B with SARS-CoV spike glycoprotein and SARS-CoV-2 papain-like protease were performed using Schrödinger. Stability of complexes followed the order 6M0J-Withanolide A > 6W9C-Withnaolide B > 5WRG-Withanolide B > 6LU7-Withanolide A. Maximum stable interaction(s) were observed between Withanolides A and B with SARS-CoV-2 and SARS-CoV spike glycoproteins, respectively. Withanolides A and B also displayed potent binding to pro-inflammatory markers viz. serum ferritin and IL-6. Thus, WS phytoconstituents have the potential to be tested further in vitro and in vivo as novel antiviral agents against COVID-19 patients having cancer as a co-morbidity.</p><p><strong>Graphical abstract: </strong></p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-023-00184-y.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"12 1","pages":"14"},"PeriodicalIF":0.0000,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10897645/pdf/","citationCount":"0","resultStr":"{\"title\":\"Steroidal lactones from <i>Withania somnifera</i> effectively target Beta, Gamma, Delta and Omicron variants of SARS-CoV-2 and reveal a decreased susceptibility to viral infection and perpetuation: a polypharmacology approach.\",\"authors\":\"Aditi Srivastava, Rumana Ahmad, Irshad A Wani, Sahabjada Siddiqui, Kusum Yadav, Anchal Trivedi, Shivbrat Upadhyay, Ishrat Husain, Tanveer Ahamad, Shivanand S Dudhagi\",\"doi\":\"10.1007/s40203-023-00184-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Prevention from disease is presently the cornerstone of the fight against COVID-19. With the rapid emergence of novel SARS-CoV-2 variants, there is an urgent need for novel or repurposed agents to strengthen and fortify the immune system. Existing vaccines induce several systemic and local side-effects that can lead to severe consequences. Moreover, elevated cytokines in COVID-19 patients with cancer as co-morbidity represent a significant bottleneck in disease prognosis and therapy. <i>Withania somnifera</i> (WS) and its phytoconstituent(s) have immense untapped immunomodulatory and therapeutic potential and the anticancer potential of WS is well documented. To this effect, WS methanolic extract (WSME) was characterized using HPLC. Withanolides were identified as the major phytoconstituents. In vitro cytotoxicity of WSME was determined against human breast MDA-MB-231 and normal Vero cells using MTT assay. WSME displayed potent cytotoxicity against MDA-MB-231 cells (IC<sub>50</sub>: 66 µg/mL) and no effect on Vero cells in the above range. MD simulations of Withanolide A with SARS-CoV-2 main protease and spike receptor-binding domain as well as Withanolide B with SARS-CoV spike glycoprotein and SARS-CoV-2 papain-like protease were performed using Schrödinger. Stability of complexes followed the order 6M0J-Withanolide A > 6W9C-Withnaolide B > 5WRG-Withanolide B > 6LU7-Withanolide A. Maximum stable interaction(s) were observed between Withanolides A and B with SARS-CoV-2 and SARS-CoV spike glycoproteins, respectively. Withanolides A and B also displayed potent binding to pro-inflammatory markers viz. serum ferritin and IL-6. Thus, WS phytoconstituents have the potential to be tested further in vitro and in vivo as novel antiviral agents against COVID-19 patients having cancer as a co-morbidity.</p><p><strong>Graphical abstract: </strong></p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-023-00184-y.</p>\",\"PeriodicalId\":94038,\"journal\":{\"name\":\"In silico pharmacology\",\"volume\":\"12 1\",\"pages\":\"14\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-02-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10897645/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"In silico pharmacology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1007/s40203-023-00184-y\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"In silico pharmacology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1007/s40203-023-00184-y","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
摘要
目前，预防疾病是抗击 COVID-19 的基石。随着新型 SARS-CoV-2 变体的迅速出现，迫切需要新型或重新确定用途的制剂来加强和强化免疫系统。现有的疫苗会引起多种全身和局部副作用，导致严重后果。此外，合并癌症的 COVID-19 患者体内细胞因子的升高也是疾病预后和治疗的一大瓶颈。睡茄（WS）及其植物成分具有尚未开发的巨大免疫调节和治疗潜力，睡茄的抗癌潜力已得到充分证实。为此，我们使用 HPLC 对 WS 代谢提取物（WSME）进行了表征。经鉴定，WSME 的主要植物成分为 Withanolides。利用 MTT 试验测定了 WSME 对人类乳腺 MDA-MB-231 细胞和正常 Vero 细胞的体外细胞毒性。WSME 对 MDA-MB-231 细胞具有很强的细胞毒性（IC50：66 µg/mL），而在上述范围内对 Vero 细胞没有影响。使用 Schrödinger 对 Withanolide A 与 SARS-CoV-2 主蛋白酶和尖峰受体结合域以及 Withanolide B 与 SARS-CoV 尖峰糖蛋白和 SARS-CoV-2 类木瓜蛋白酶进行了 MD 模拟。复合物的稳定性顺序为 6M0J-Withanolide A > 6W9C-Withnaolide B > 5WRG-Withanolide B > 6LU7-Withanolide A。在 Withanolides A 和 B 与 SARS-CoV-2 和 SARS-CoV 穗糖蛋白之间分别观察到了最稳定的相互作用。Withanolides A 和 B 还显示出与促炎标志物（即血清铁蛋白和 IL-6）的强效结合。因此，WS 植物成分有可能作为新型抗病毒药物在体外和体内对 COVID-19 合并癌症患者进行进一步测试：在线版本包含补充材料，可在10.1007/s40203-023-00184-y上获取。
Steroidal lactones from Withania somnifera effectively target Beta, Gamma, Delta and Omicron variants of SARS-CoV-2 and reveal a decreased susceptibility to viral infection and perpetuation: a polypharmacology approach.
Prevention from disease is presently the cornerstone of the fight against COVID-19. With the rapid emergence of novel SARS-CoV-2 variants, there is an urgent need for novel or repurposed agents to strengthen and fortify the immune system. Existing vaccines induce several systemic and local side-effects that can lead to severe consequences. Moreover, elevated cytokines in COVID-19 patients with cancer as co-morbidity represent a significant bottleneck in disease prognosis and therapy. Withania somnifera (WS) and its phytoconstituent(s) have immense untapped immunomodulatory and therapeutic potential and the anticancer potential of WS is well documented. To this effect, WS methanolic extract (WSME) was characterized using HPLC. Withanolides were identified as the major phytoconstituents. In vitro cytotoxicity of WSME was determined against human breast MDA-MB-231 and normal Vero cells using MTT assay. WSME displayed potent cytotoxicity against MDA-MB-231 cells (IC50: 66 µg/mL) and no effect on Vero cells in the above range. MD simulations of Withanolide A with SARS-CoV-2 main protease and spike receptor-binding domain as well as Withanolide B with SARS-CoV spike glycoprotein and SARS-CoV-2 papain-like protease were performed using Schrödinger. Stability of complexes followed the order 6M0J-Withanolide A > 6W9C-Withnaolide B > 5WRG-Withanolide B > 6LU7-Withanolide A. Maximum stable interaction(s) were observed between Withanolides A and B with SARS-CoV-2 and SARS-CoV spike glycoproteins, respectively. Withanolides A and B also displayed potent binding to pro-inflammatory markers viz. serum ferritin and IL-6. Thus, WS phytoconstituents have the potential to be tested further in vitro and in vivo as novel antiviral agents against COVID-19 patients having cancer as a co-morbidity.
Graphical abstract:
Supplementary information: The online version contains supplementary material available at 10.1007/s40203-023-00184-y.
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