Computational Evidence for Bisartan Arginine Blockers as Next-Generation Pan-Antiviral Therapeutics Targeting SARS-CoV-2, Influenza, and Respiratory Syncytial Viruses.

IF 3.8 3区 医学 Q2 VIROLOGY Viruses-Basel Pub Date : 2024-11-14 DOI:10.3390/v16111776
Harry Ridgway, Vasso Apostolopoulos, Graham J Moore, Laura Kate Gadanec, Anthony Zulli, Jordan Swiderski, Sotirios Tsiodras, Konstantinos Kelaidonis, Christos T Chasapis, John M Matsoukas
{"title":"Computational Evidence for Bisartan Arginine Blockers as Next-Generation Pan-Antiviral Therapeutics Targeting SARS-CoV-2, Influenza, and Respiratory Syncytial Viruses.","authors":"Harry Ridgway, Vasso Apostolopoulos, Graham J Moore, Laura Kate Gadanec, Anthony Zulli, Jordan Swiderski, Sotirios Tsiodras, Konstantinos Kelaidonis, Christos T Chasapis, John M Matsoukas","doi":"10.3390/v16111776","DOIUrl":null,"url":null,"abstract":"<p><p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza, and respiratory syncytial virus (RSV) are significant global health threats. The need for low-cost, easily synthesized oral drugs for rapid deployment during outbreaks is crucial. Broad-spectrum therapeutics, or pan-antivirals, are designed to target multiple viral pathogens simultaneously by focusing on shared molecular features, such as common metal cofactors or conserved residues in viral catalytic domains. This study introduces a new generation of potent sartans, known as bisartans, engineered in our laboratories with negative charges from carboxylate or tetrazolate groups. These anionic tetrazoles interact strongly with cationic arginine residues or metal cations (e.g., Zn<sup>2+</sup>) within viral and host target sites, including the SARS-CoV-2 ACE2 receptor, influenza H1N1 neuraminidases, and the RSV fusion protein. Using virtual ligand docking and molecular dynamics, we investigated how bisartans and their analogs bind to these viral receptors, potentially blocking infection through a pan-antiviral mechanism. Bisartan, ACC519TT, demonstrated stable and high-affinity docking to key catalytic domains of the SARS-CoV-2 NSP3, H1N1 neuraminidase, and RSV fusion protein, outperforming FDA-approved drugs like Paxlovid and oseltamivir. It also showed strong binding to the arginine-rich furin cleavage sites S1/S2 and S2', suggesting interference with SARS-CoV-2's spike protein cleavage. The results highlight the potential of tetrazole-based bisartans as promising candidates for developing broad-spectrum antiviral therapies.</p>","PeriodicalId":49328,"journal":{"name":"Viruses-Basel","volume":"16 11","pages":""},"PeriodicalIF":3.8000,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11599072/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Viruses-Basel","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3390/v16111776","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"VIROLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza, and respiratory syncytial virus (RSV) are significant global health threats. The need for low-cost, easily synthesized oral drugs for rapid deployment during outbreaks is crucial. Broad-spectrum therapeutics, or pan-antivirals, are designed to target multiple viral pathogens simultaneously by focusing on shared molecular features, such as common metal cofactors or conserved residues in viral catalytic domains. This study introduces a new generation of potent sartans, known as bisartans, engineered in our laboratories with negative charges from carboxylate or tetrazolate groups. These anionic tetrazoles interact strongly with cationic arginine residues or metal cations (e.g., Zn2+) within viral and host target sites, including the SARS-CoV-2 ACE2 receptor, influenza H1N1 neuraminidases, and the RSV fusion protein. Using virtual ligand docking and molecular dynamics, we investigated how bisartans and their analogs bind to these viral receptors, potentially blocking infection through a pan-antiviral mechanism. Bisartan, ACC519TT, demonstrated stable and high-affinity docking to key catalytic domains of the SARS-CoV-2 NSP3, H1N1 neuraminidase, and RSV fusion protein, outperforming FDA-approved drugs like Paxlovid and oseltamivir. It also showed strong binding to the arginine-rich furin cleavage sites S1/S2 and S2', suggesting interference with SARS-CoV-2's spike protein cleavage. The results highlight the potential of tetrazole-based bisartans as promising candidates for developing broad-spectrum antiviral therapies.

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
将比沙坦精氨酸阻断剂作为针对 SARS-CoV-2、流感和呼吸道合胞病毒的下一代泛抗病毒疗法的计算证据。
严重急性呼吸系统综合征冠状病毒 2(SARS-CoV-2)、流感和呼吸道合胞病毒(RSV)是全球健康的重大威胁。亟需低成本、易合成的口服药物,以便在疫情爆发时快速部署。广谱疗法或泛抗病毒药物是通过关注共同的分子特征(如病毒催化结构域中常见的金属辅助因子或保守残基),同时针对多种病毒病原体而设计的。本研究介绍了我们实验室设计的新一代强效沙坦类药物--双沙坦类药物,它们带有羧酸或四唑基负电荷。这些阴离子四唑与病毒和宿主靶位点内的阳离子精氨酸残基或金属阳离子(如 Zn2+)有强烈的相互作用,这些靶位点包括 SARS-CoV-2 ACE2 受体、H1N1 流感神经氨酸酶和 RSV 融合蛋白。利用虚拟配体对接和分子动力学,我们研究了比沙坦及其类似物如何与这些病毒受体结合,从而可能通过泛抗病毒机制阻断感染。比沙坦 ACC519TT 与 SARS-CoV-2 NSP3、H1N1 神经氨酸苷酶和 RSV 融合蛋白的关键催化结构域进行了稳定和高亲和力的对接,表现优于 Paxlovid 和奥司他韦等 FDA 批准的药物。它还显示出与富含精氨酸的呋喃裂解位点 S1/S2 和 S2'的强结合力,表明它能干扰 SARS-CoV-2 的尖峰蛋白裂解。这些结果凸显了以四唑为基础的双artans作为开发广谱抗病毒疗法的候选药物的潜力。
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
Viruses-Basel
Viruses-Basel VIROLOGY-
CiteScore
7.30
自引率
12.80%
发文量
2445
审稿时长
1 months
期刊介绍: Viruses (ISSN 1999-4915) is an open access journal which provides an advanced forum for studies of viruses. It publishes reviews, regular research papers, communications, conference reports and short notes. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced. We also encourage the publication of timely reviews and commentaries on topics of interest to the virology community and feature highlights from the virology literature in the ''News and Views'' section. Electronic files or software regarding the full details of the calculation and experimental procedure, if unable to be published in a normal way, can be deposited as supplementary material.
期刊最新文献
Phylogenomic Signatures of a Lineage of Vesicular Stomatitis Indiana Virus Circulating During the 2019-2020 Epidemic in the United States. Assessment of Bacteriophage Pharmacokinetic Parameters After Intra-Articular Delivery in a Rat Prosthetic Joint Infection Model. Chimeric Virus-like Particles of Physalis Mottle Virus as Carriers of M2e Peptides of Influenza a Virus. Investigation of Polymorphisms Induced by the Solo Long Terminal Repeats (Solo-LTRs) in Porcine Endogenous Retroviruses (ERVs). Unveiling the Role of TMPRSS2 in the Proteolytic Activation of Pandemic and Zoonotic Influenza Viruses and Coronaviruses in Human Airway Cells.
×
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