Potential role of PIM1 inhibition in the treatment of SARS-CoV-2 infection.

IF 3.6 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Journal, genetic engineering & biotechnology Pub Date : 2023-05-22 DOI:10.1186/s43141-023-00520-x
Magda M F Ismail, Rehab R El-Awady, Amal M Farrag, Sara H Mahmoud, Noura M Abo Shama, Ahmed Mostafa, Mohamed A Ali, Mohammed H Rashed, Iman H Ibrahim
{"title":"Potential role of PIM1 inhibition in the treatment of SARS-CoV-2 infection.","authors":"Magda M F Ismail, Rehab R El-Awady, Amal M Farrag, Sara H Mahmoud, Noura M Abo Shama, Ahmed Mostafa, Mohamed A Ali, Mohammed H Rashed, Iman H Ibrahim","doi":"10.1186/s43141-023-00520-x","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>SARS-CoV-2 infection involves disturbing multiple molecular pathways related to immunity and cellular functions. PIM1 is a serine/threonine-protein kinase found to be involved in the pathogenesis of several viral infections. One PIM1 substrate, Myc, was reported to interact with TMPRSS2, which is crucial for SARS-CoV-2 cell entry. PIM1 inhibitors were reported to have antiviral activity through multiple mechanisms related to immunity and proliferation. This study aimed to evaluate the antiviral activity of 2-pyridone PIM1 inhibitor against SARS-CoV-2 and its potential role in hindering the progression of COVID-19. It also aimed to assess PIM1 inhibitor's effect on the expression of several genes of Notch signaling and Wnt pathways. In vitro study was conducted on Vero-E6 cells infected by SARS-CoV-2 \"NRC-03-nhCoV\" virus. Protein-protein interaction of the study genes was assessed to evaluate their relation to cell proliferation and immunity. The effect of 2-pyridone PIM1 inhibitor treatment on viral load and mRNA expression of target genes was assessed at three time points.</p><p><strong>Results: </strong>Treatment with 2-pyridone PIM1 inhibitor showed potential antiviral activity against SARS-CoV-2 (IC<sub>50</sub> of 37.255 µg/ml), significantly lowering the viral load. Functional enrichments of the studied genes include negative regulation of growth rate, several biological processes involved in cell proliferation, and Interleukin-4 production, with interleukin-6 as a predicted functional partner. These results suggest an interplay between study genes with relation to cell proliferation and immunity. Following in vitro SARS-CoV-2 infection, Notch pathway genes, CTNNB1, SUMO1, and TDG, were found to be overexpressed compared to uninfected cells. Treatment with 2-pyridone PIM1 inhibitor significantly lowers the expression levels of study genes, restoring Notch1 and BCL9 to the control level while decreasing Notch2 and CTNNB1 below control levels.</p><p><strong>Conclusion: </strong>2-pyridone PIM1 inhibitor could hinder cellular entry of SARS-CoV-2 and modulate several pathways implicated in immunity, suggesting a potential benefit in the development of anti-SARS-CoV-2 therapeutic approach.</p>","PeriodicalId":74026,"journal":{"name":"Journal, genetic engineering & biotechnology","volume":null,"pages":null},"PeriodicalIF":3.6000,"publicationDate":"2023-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10200336/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal, genetic engineering & biotechnology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1186/s43141-023-00520-x","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Background: SARS-CoV-2 infection involves disturbing multiple molecular pathways related to immunity and cellular functions. PIM1 is a serine/threonine-protein kinase found to be involved in the pathogenesis of several viral infections. One PIM1 substrate, Myc, was reported to interact with TMPRSS2, which is crucial for SARS-CoV-2 cell entry. PIM1 inhibitors were reported to have antiviral activity through multiple mechanisms related to immunity and proliferation. This study aimed to evaluate the antiviral activity of 2-pyridone PIM1 inhibitor against SARS-CoV-2 and its potential role in hindering the progression of COVID-19. It also aimed to assess PIM1 inhibitor's effect on the expression of several genes of Notch signaling and Wnt pathways. In vitro study was conducted on Vero-E6 cells infected by SARS-CoV-2 "NRC-03-nhCoV" virus. Protein-protein interaction of the study genes was assessed to evaluate their relation to cell proliferation and immunity. The effect of 2-pyridone PIM1 inhibitor treatment on viral load and mRNA expression of target genes was assessed at three time points.

Results: Treatment with 2-pyridone PIM1 inhibitor showed potential antiviral activity against SARS-CoV-2 (IC50 of 37.255 µg/ml), significantly lowering the viral load. Functional enrichments of the studied genes include negative regulation of growth rate, several biological processes involved in cell proliferation, and Interleukin-4 production, with interleukin-6 as a predicted functional partner. These results suggest an interplay between study genes with relation to cell proliferation and immunity. Following in vitro SARS-CoV-2 infection, Notch pathway genes, CTNNB1, SUMO1, and TDG, were found to be overexpressed compared to uninfected cells. Treatment with 2-pyridone PIM1 inhibitor significantly lowers the expression levels of study genes, restoring Notch1 and BCL9 to the control level while decreasing Notch2 and CTNNB1 below control levels.

Conclusion: 2-pyridone PIM1 inhibitor could hinder cellular entry of SARS-CoV-2 and modulate several pathways implicated in immunity, suggesting a potential benefit in the development of anti-SARS-CoV-2 therapeutic approach.

Abstract Image

Abstract Image

Abstract Image

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
PIM1 抑制剂在治疗 SARS-CoV-2 感染中的潜在作用。
背景:SARS-CoV-2 感染会扰乱与免疫和细胞功能有关的多种分子通路。PIM1是一种丝氨酸/苏氨酸蛋白激酶,被发现参与了多种病毒感染的发病机制。据报道,PIM1 的一个底物 Myc 与 TMPRSS2 相互作用,而 TMPRSS2 对 SARS-CoV-2 细胞的进入至关重要。据报道,PIM1 抑制剂通过与免疫和增殖相关的多种机制具有抗病毒活性。本研究旨在评估 2-吡啶酮 PIM1 抑制剂对 SARS-CoV-2 的抗病毒活性及其在阻碍 COVID-19 进展方面的潜在作用。研究还旨在评估 PIM1 抑制剂对 Notch 信号和 Wnt 通路中多个基因表达的影响。体外研究是在感染了 SARS-CoV-2 "NRC-03-nhCoV "病毒的 Vero-E6 细胞上进行的。对研究基因的蛋白质相互作用进行了评估,以评价它们与细胞增殖和免疫的关系。在三个时间点评估了 2-pyridone PIM1 抑制剂处理对病毒载量和目标基因 mRNA 表达的影响:结果:2-吡啶酮 PIM1 抑制剂对 SARS-CoV-2 有潜在的抗病毒活性(IC50 为 37.255 µg/ml),能显著降低病毒载量。所研究基因的功能富集包括生长率的负调控、涉及细胞增殖的几个生物过程和白细胞介素-4的产生,白细胞介素-6是预测的功能伙伴。这些结果表明,研究基因之间的相互作用与细胞增殖和免疫有关。体外 SARS-CoV-2 感染后,发现 Notch 通路基因 CTNNB1、SUMO1 和 TDG 与未感染细胞相比表达过高。结论:2-吡啶酮 PIM1 抑制剂能阻碍 SARS-CoV-2 进入细胞,并调节与免疫有关的几种通路,这表明它可能有利于开发抗 SARS-CoV-2 治疗方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
自引率
0.00%
发文量
0
期刊最新文献
Physiochemical analyses and molecular characterization of heavy metal-resistant bacteria from Ilesha gold mining sites in Nigeria. Whole genome sequence and comparative genomics analysis of multidrug-resistant Staphylococcus xylosus NM36 isolated from a cow with mastitis in Basrah city. Immunoinformatics-aided rational design of multiepitope-based peptide vaccine (MEBV) targeting human parainfluenza virus 3 (HPIV-3) stable proteins. Isolation of plant growth-promoting rhizobacteria from the agricultural fields of Tattiannaram, Telangana. Short tandem repeat (STR) variation from 6 cities in Iraq based on 15 loci.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1