Antiviral research最新文献_第8页

Preventing human influenza and coronaviral mono or coinfection by blocking virus-induced sialylation 通过阻断病毒诱导的 Sialylation 来预防人类流感和冠状病毒的单一或混合感染。

IF 4.5 2区医学

Antiviral research Pub Date : 2024-12-01 DOI: 10.1016/j.antiviral.2024.106041

Md Ruhul Amin , Khandaker N. Anwar , M.J. Ashraf , Mahmood Ghassemi , Richard M. Novak

{"title":"Preventing human influenza and coronaviral mono or coinfection by blocking virus-induced sialylation","authors":"Md Ruhul Amin , Khandaker N. Anwar , M.J. Ashraf , Mahmood Ghassemi , Richard M. Novak","doi":"10.1016/j.antiviral.2024.106041","DOIUrl":"10.1016/j.antiviral.2024.106041","url":null,"abstract":"<div><div>Influenza A viruses (IAVs) and endemic coronaviruses (eCoVs) are common etiologic agents for seasonal respiratory infections. The human H1N1 of IAV and coronavirus OC43 (HCoV-OC43) can result in hospitalization, acute respiratory distress syndrome (ARDS), and even death, particularly in immunocompromised individuals. They infect the epithelium of the respiratory tract by interacting with host cell sialic acid (Sia)- linked receptors whose synthesis is catalyzed by sialyltransferases (STs). Viral coinfection is challenging to treat because of the need to target specific components of two or more distinct pathogens. Emerging drug and vaccine resistance due to the high mutation rate of viral genomes further complicates the treatment and prevention of viral infection. Sialylation mediated by STs may be a potential drug target for treating viral diseases. ST is an attractive target because it could be effective before identifying the pathogen that has occurred, providing a novel direction for overcoming drug resistance and achieving a broad-spectrum antiviral effect. We developed an H1N1 and OC43 mono or coinfection model using 14 days post-plating (14 PP) human primary small airway epithelial cells (HSAEC) grown on transwell inserts at an air-fluid interface (ALI), mimicking in vivo cellular dynamics. Using this model, we have observed that mono or coinfection with OC43 and H1N1 results in increased sialic acid levels and synergistic viral infection. We showed for the first time that H1N1 and OC43 mono- and coinfection in HSAEC caused increased expression and activity of STs, which can be blocked by pan-STs inhibitor (3Fax-Peracetyl Neu5Ac) with no host cell toxicity.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"232 ","pages":"Article 106041"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development of lipopeptide-based HIV-1/2 fusion inhibitors targeting the gp41 pocket site with a new design strategy 用新的设计策略开发基于脂肽的 HIV-1/2 融合抑制剂，靶向 gp41 口袋位点。

IF 4.5 2区医学

Antiviral research Pub Date : 2024-12-01 DOI: 10.1016/j.antiviral.2024.106042

Xiuzhu Geng , Yuanmei Zhu , Yue Gao , Huihui Chong , Yuxian He

{"title":"Development of lipopeptide-based HIV-1/2 fusion inhibitors targeting the gp41 pocket site with a new design strategy","authors":"Xiuzhu Geng , Yuanmei Zhu , Yue Gao , Huihui Chong , Yuxian He","doi":"10.1016/j.antiviral.2024.106042","DOIUrl":"10.1016/j.antiviral.2024.106042","url":null,"abstract":"<div><div>Emerging studies demonstrate that lipid conjugation is a vital strategy for designing peptide-based viral fusion inhibitors, and the so-called lipopeptides exhibit greatly improved antiviral activity. In the design of lipopeptides, a flexible linker between the peptide sequence and lipid molecule is generally required, mostly with a short polyethylene glycol or glycine-serine sequence. Very recently, we discovered that the helix-facilitating amino acid sequence “EAAAK” as a rigid linker is a more efficient method in the design of SARS-CoV-2 fusion inhibitory lipopeptides. In this study, we comprehensively characterized the functionalities of different linkers in HIV fusion inhibitors. A short-peptide inhibitor 2P23, which mainly targets the gp41 pocket site, was used as a design template, generating a group of cholesterol-modified lipopeptides. In the inhibition of HIV-1 infection, the lipopeptide inhibitors with a rigid linker were much superior than those with the flexible linkers, as indicated by LP-37 with the “EAAAK” linker and LP-39 with the repeated “EP” amino acid sequences. Both lipopeptides were very potent inhibitors of HIV-2 and simian immunodeficiency (SIV) either. Promisingly, LP-37 displayed high α-helicity, thermostability and binding ability to a target-mimic peptide, and it was metabolically stable when treated with temperature, proteolytic enzymes or human sera. Taken together, our studies have verified a universal strategy for designing viral fusion inhibitors and offered a novel HIV fusion inhibitor for drug development.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"232 ","pages":"Article 106042"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Biological characterization of AB-343, a novel and potent SARS-CoV-2 Mpro inhibitor with pan-coronavirus activity 具有泛冠状病毒活性的新型强效 SARS-CoV-2 Mpro 抑制剂 AB-343 的生物学特性。

IF 4.5 2区医学

Antiviral research Pub Date : 2024-11-20 DOI: 10.1016/j.antiviral.2024.106038

Kayleigh R. McGovern-Gooch , Nagraj Mani , Dimitar Gotchev , Andrzej Ardzinski , Rose Kowalski , Muhammad Sheraz , Holly M. Micolochick Steuer , Breanna Tercero , Xiaohe Wang , Adam Wasserman , Chia-yi Chen , Konstanze von König , Klaus Maskos , Archna Prasad , Michael Blaesse , Andreas Bergmann , Debora L. Konz Makino , Kristi Y. Fan , Steven G. Kultgen , Aaron Lindstrom , Michael J. Sofia

{"title":"Biological characterization of AB-343, a novel and potent SARS-CoV-2 Mpro inhibitor with pan-coronavirus activity","authors":"Kayleigh R. McGovern-Gooch , Nagraj Mani , Dimitar Gotchev , Andrzej Ardzinski , Rose Kowalski , Muhammad Sheraz , Holly M. Micolochick Steuer , Breanna Tercero , Xiaohe Wang , Adam Wasserman , Chia-yi Chen , Konstanze von König , Klaus Maskos , Archna Prasad , Michael Blaesse , Andreas Bergmann , Debora L. Konz Makino , Kristi Y. Fan , Steven G. Kultgen , Aaron Lindstrom , Michael J. Sofia","doi":"10.1016/j.antiviral.2024.106038","DOIUrl":"10.1016/j.antiviral.2024.106038","url":null,"abstract":"<div><div>Since the SARS-CoV-2 outbreak, there have been ongoing efforts to identify antiviral molecules with broad coronavirus activity to combat COVID-19. SARS-CoV-2's main protease (M<sup>pro</sup>) is responsible for processing the viral polypeptide into non-structural proteins essential for replication. Here, we present the biological characterization of AB-343, a covalent small-molecule inhibitor of SARS-CoV-2 M<sup>pro</sup> with potent activity in both cell-based (EC<sub>50</sub> = 0.018 μM) and enzymatic (K<sub><em>i</em></sub> = 0.0028 μM) assays. AB-343 also demonstrated excellent inhibition of M<sup>pro</sup> of other human coronaviruses, including those from the alpha (229E and NL63) and beta (SARS-CoV, MERS, OC43, and HKU1) families, suggesting the compound could be active against future coronaviruses. No change in AB-343 potency was observed against M<sup>pro</sup> of SARS-CoV-2 variants of concern, including Omicron, suggesting that AB-343 could be developed as a treatment against currently circulating coronaviruses. AB-343 also remained active against several M<sup>pro</sup> variants which confer significant resistance to nirmatrelvir and ensitrelvir, which are presently the only M<sup>pro</sup> inhibitors authorized for the treatment of COVID-19, further supporting the evaluation of AB-343 as a novel and potent therapeutic for COVID-19 and other coronaviruses.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"232 ","pages":"Article 106038"},"PeriodicalIF":4.5,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

X-206 exhibits broad-spectrum anti-β-coronavirus activity, covering SARS-CoV-2 variants and drug-resistant isolates X-206 具有广谱的抗β-冠状病毒活性，涵盖 SARS-CoV-2 变体和耐药分离株。

IF 4.5 2区医学

Antiviral research Pub Date : 2024-11-19 DOI: 10.1016/j.antiviral.2024.106039

Jiei Sasaki , Akihiko Sato , Michihito Sasaki , Iori Okabe , Kota Kodama , Satoko Otsuguro , Kosuke Yasuda , Hirotatsu Kojima , Yasuko Orba , Hirofumi Sawa , Katsumi Maenaka , Yusuke Yanagi , Takao Hashiguchi

{"title":"X-206 exhibits broad-spectrum anti-β-coronavirus activity, covering SARS-CoV-2 variants and drug-resistant isolates","authors":"Jiei Sasaki , Akihiko Sato , Michihito Sasaki , Iori Okabe , Kota Kodama , Satoko Otsuguro , Kosuke Yasuda , Hirotatsu Kojima , Yasuko Orba , Hirofumi Sawa , Katsumi Maenaka , Yusuke Yanagi , Takao Hashiguchi","doi":"10.1016/j.antiviral.2024.106039","DOIUrl":"10.1016/j.antiviral.2024.106039","url":null,"abstract":"<div><div>Coronaviruses such as the Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and SARS-CoV-2, causing MERS, SARS, and Coronavirus disease-19, respectively, are highly pathogenic to humans. Notably, several antiviral drugs against SARS-CoV-2, such as nirmatrelvir and remdesivir, have been approved. However, no approved vaccines or antiviral agents are available for other highly pathogenic β-coronaviruses. In this study, we identified two compounds, thapsigargin and X-206, that exhibit antiviral activities against SARS-CoV, MERS-CoV, and SARS-CoV-2. Notably, both compounds effectively inhibited the cell-to-cell fusion mediated by the Spike proteins of all three β−coronaviruses. X-206 exhibited antiviral activity against nirmatrelvir- and remdesivir-resistant SARS-CoV-2 isolates and SARS-CoV-2 variants, including Delta, BA.5, and XBB.1. Consequently, the mechanism of action of these compounds with anti-β-coronavirus activities may differ from that of the approved direct-acting drugs for SARS-CoV-2, thereby offering potential use as a cocktail with other antivirals, and serving as a chemical basis for developing therapeutic agents against β−coronaviruses in preparation for the next spillover and pandemic.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"232 ","pages":"Article 106039"},"PeriodicalIF":4.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Meeting report of the 37th International Conference on Antiviral Research in Gold Coast, Australia, May 20–24, 2024, organized by the International Society for Antiviral Research 国际抗病毒研究学会于 2024 年 5 月 20-24 日在澳大利亚黄金海岸举办的第 37 届国际抗病毒研究大会的会议报告。

IF 4.5 2区医学

Antiviral research Pub Date : 2024-11-13 DOI: 10.1016/j.antiviral.2024.106037

Stephen R. Welch , John P. Bilello , Kara Carter , Leen Delang , Larissa Dirr , David Durantel , Joy Y. Feng , Brian B. Gowen , Lara J. Herrero , Zlatko Janeba , Gerald Kleymann , Alpha A. Lee , Chris Meier , Jennifer Moffat , Luis M. Schang , Joshua T. Schiffer , Katherine L. Seley-Radtke , Timothy P. Sheahan , Jessica R. Spengler

{"title":"Meeting report of the 37th International Conference on Antiviral Research in Gold Coast, Australia, May 20–24, 2024, organized by the International Society for Antiviral Research","authors":"Stephen R. Welch , John P. Bilello , Kara Carter , Leen Delang , Larissa Dirr , David Durantel , Joy Y. Feng , Brian B. Gowen , Lara J. Herrero , Zlatko Janeba , Gerald Kleymann , Alpha A. Lee , Chris Meier , Jennifer Moffat , Luis M. Schang , Joshua T. Schiffer , Katherine L. Seley-Radtke , Timothy P. Sheahan , Jessica R. Spengler","doi":"10.1016/j.antiviral.2024.106037","DOIUrl":"10.1016/j.antiviral.2024.106037","url":null,"abstract":"<div><div>The 37th International Conference on Antiviral Research (ICAR) was held in Gold Coast, Australia, May 20–24, 2024. ICAR 2024 featured over 75 presentations along with two poster sessions and special events, including those specifically tailored for trainees and early-career scientists. The meeting served as a platform for the exchange of cutting-edge research, with presentations and discussions covering novel antiviral compounds, vaccine development, clinical trials, and therapeutic advancements. A comprehensive array of topics in antiviral science was covered, from the latest breakthroughs in antiviral drug development to innovative strategies for combating emerging viral threats. The keynote presentations provided fascinating insight into two diverse areas fundamental to medical countermeasure development and use, including virus emergence at the human-animal interface and practical considerations for bringing antivirals to the clinic. Additional sessions addressed a variety of timely post-pandemic topics, such as the hunt for broad spectrum antivirals, combination therapy, pandemic preparedness, application of in silico tools and AI in drug discovery, the virosphere, and more. Here, we summarize all the presentations and special sessions of ICAR 2024 and introduce the 38th ICAR, which will be held in Las Vegas, USA, March 17–21, 2025.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"232 ","pages":"Article 106037"},"PeriodicalIF":4.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The anti-tumor efficacy of a recombinant oncolytic herpes simplex virus mediated CRISPR/Cas9 delivery targeting in HPV16-positive cervical cancer 重组单纯疱疹病毒介导的 CRISPR/Cas9 递送靶向药物对 HPV16 阳性宫颈癌的抗肿瘤疗效。

IF 4.5 2区医学

Antiviral research Pub Date : 2024-11-12 DOI: 10.1016/j.antiviral.2024.106035

Zongfeng Hu , Wenqi Liu , Jiajia Liu , Hua Zhou , Chunyang Sun , ChaoTian , Xiaona Guo , Chengyang Zhu , Mingxia Shao , Shengrun Wang , Lijun Wei , Min Liu , Shuzhen Li , Jinyu Wang , Haitian Xu , Wei Zhu , Xiaopeng Li , Jingfeng Li

{"title":"The anti-tumor efficacy of a recombinant oncolytic herpes simplex virus mediated CRISPR/Cas9 delivery targeting in HPV16-positive cervical cancer","authors":"Zongfeng Hu , Wenqi Liu , Jiajia Liu , Hua Zhou , Chunyang Sun , ChaoTian , Xiaona Guo , Chengyang Zhu , Mingxia Shao , Shengrun Wang , Lijun Wei , Min Liu , Shuzhen Li , Jinyu Wang , Haitian Xu , Wei Zhu , Xiaopeng Li , Jingfeng Li","doi":"10.1016/j.antiviral.2024.106035","DOIUrl":"10.1016/j.antiviral.2024.106035","url":null,"abstract":"<div><div>Cervical cancer, often driven by high-risk human papillomavirus (HPV) infections such as HPV16 or HPV18, remains a leading cause of cancer-related deaths. HPV16, found in about 90% of cervical cancer patients, harbors key oncogenic related genes (E6, E7, E2, E5) and an upstream regulatory region (URR) that contribute to cancer progression. This study introduces a novel approach using a recombinant oncolytic herpes simplex virus type 1 (HSV-1) named SONC103, armed with a CRISPR/Cas9 gene editing system. The aim was to target and disrupt integrated HPV16 genes in cervical cancer cells. Results demonstrated SONC103's capability to specifically and effectively knock down HPV16 oncogenes, thereby reducing cell proliferation and promoting apoptosis. Analyses further revealed loss of HPV16 DNA probes in infected cells' chromosomes, significant regulation of cellular processes related to tumor apoptosis, and downregulation of E6/E7 oncoproteins while increasing tumor suppressor proteins P53 and pRB. Notably, SONC103 exhibited substantial inhibition of tumor growth in a murine xenograft cervical cancer model. This study showcases the potential of the recombinant oncolytic HSV-1 virus (SONC103) in combating HPV16-positive cervical cancer by targeting oncogenes and facilitating oncolysis.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"232 ","pages":"Article 106035"},"PeriodicalIF":4.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A rapid and versatile reverse genetic approach and visualization animal models for emerging zoonotic pseudorabies virus 针对新出现的人畜共患伪狂犬病病毒的快速多用途反向遗传方法和可视化动物模型。

IF 4.5 2区医学

Antiviral research Pub Date : 2024-11-08 DOI: 10.1016/j.antiviral.2024.106036

Yu Zhang , Xiangtong Li , Juan Zhang , Yueyue Duan , Peibin Chen , Lei Shi , Cong Yuan , Liyan Cao , Maowen Sun , Yating Wang , Xiangyu Kong , Haixue Zheng , Qi Wang

{"title":"A rapid and versatile reverse genetic approach and visualization animal models for emerging zoonotic pseudorabies virus","authors":"Yu Zhang , Xiangtong Li , Juan Zhang , Yueyue Duan , Peibin Chen , Lei Shi , Cong Yuan , Liyan Cao , Maowen Sun , Yating Wang , Xiangyu Kong , Haixue Zheng , Qi Wang","doi":"10.1016/j.antiviral.2024.106036","DOIUrl":"10.1016/j.antiviral.2024.106036","url":null,"abstract":"<div><div>Pseudorabies virus (PRV), a member of the Alphaherpesvirinae subfamily and a causative pathogen of Aujeszky's disease, has a broad host range including domestic and wild animals. PRV has been reported as a causative agent in patients with acute encephalitis in 2021, which suggests PRV might be a novel animal-origin virus in terms of zoonotic spillover and spread potential. To manage current PRV epidemics in pigs and prepare for future pandemics in other species including humans. Fundamental techniques essential for procuring such knowledge on prevention and therapy of PRV. Here, PRV CD22 strain was isolated and phylogenetic analysis showed that PRV CD22 belongs to the current epidemic strains in China. PRV CD22 was highly lethal to mice and piglets in vivo. Moreover, a rapid and efficient system to generate recombinant PRV was constructed based on PRV CD22 genomic DNA fosmid library. Using this system, a recombinant PRV strain expressing engineered labeling protein was rescued for visualization of viral infection in mouse model. Our study allows the generation of PRV that can be used for downstream treatment analyses. Once experimental or surveillance samples are obtained, PRV can be generated and treated efficiently based on our study.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"232 ","pages":"Article 106036"},"PeriodicalIF":4.5,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The effects of Remdesivir's functional groups on its antiviral potency and resistance against the SARS-CoV-2 polymerase 雷米替韦的官能团对其抗病毒效力和抗 SARS-CoV-2 聚合酶能力的影响。

IF 4.5 2区医学

Antiviral research Pub Date : 2024-11-05 DOI: 10.1016/j.antiviral.2024.106034

Bhawna Sama , Barbara Selisko , Camille Falcou , Véronique Fattorini , Géraldine Piorkowski , Franck Touret , Kim Donckers , Johan Neyts , Dirk Jochmans , Ashleigh Shannon , Bruno Coutard , Bruno Canard

{"title":"The effects of Remdesivir's functional groups on its antiviral potency and resistance against the SARS-CoV-2 polymerase","authors":"Bhawna Sama , Barbara Selisko , Camille Falcou , Véronique Fattorini , Géraldine Piorkowski , Franck Touret , Kim Donckers , Johan Neyts , Dirk Jochmans , Ashleigh Shannon , Bruno Coutard , Bruno Canard","doi":"10.1016/j.antiviral.2024.106034","DOIUrl":"10.1016/j.antiviral.2024.106034","url":null,"abstract":"<div><div>Remdesivir (RDV, Veklury®) is the first FDA-approved antiviral treatment for COVID-19. It is a nucleotide analogue (NA) carrying a 1′-cyano (1′-CN) group on the ribose and a pseudo-adenine nucleobase whose contributions to the mode of action (MoA) are not clear. Here, we dissect these independent contributions by employing RDV-TP analogues. We show that while the 1′-CN group is directly responsible for transient stalling of the SARS-CoV-2 replication/transcription complex (RTC), the nucleobase plays a role in the strength of this stalling. Conversely, RNA extension assays show that the 1′-CN group plays a role in fidelity and that RDV-TP can be incorporated as a GTP analogue, albeit with lower efficiency. However, a mutagenic effect by the viral polymerase is not ascertained by deep sequencing of viral RNA from cells treated with RDV. We observe that once added to the 3′ end of RNA, RDV-MP is sensitive to excision and its 1′-CN group does not impact its nsp14-mediated removal. A >14-fold RDV-resistant SARS-CoV-2 isolate can be selected carrying two mutations in the nsp12 sequence, S759A and A777S. They confer both RDV-TP discrimination over ATP by nsp12 and stalling during RNA synthesis, leaving more time for excision-repair and potentially dampening RDV efficiency. We conclude that RDV presents a multi-faced MoA. It slows down or stalls overall RNA synthesis but is efficiently repaired from the primer strand, whereas once in the template, read-through inhibition adds to this effect. Its efficient incorporation may corrupt proviral RNA, likely disturbing downstream functions in the virus life cycle.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"232 ","pages":"Article 106034"},"PeriodicalIF":4.5,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Berberine promotes K48-linked polyubiquitination of HNF4α, leading to the inhibition of HBV replication 小檗碱能促进与 K48 链接的 HNF4α 多泛素化，从而抑制 HBV 复制。

IF 4.5 2区医学

Antiviral research Pub Date : 2024-11-01 DOI: 10.1016/j.antiviral.2024.106027

Atsuya Yamashita , Hirotake Kasai , Shinya Maekawa , Tomohisa Tanaka , Yasunori Akaike , Akihide Ryo , Nobuyuki Enomoto , Kohji Moriishi

{"title":"Berberine promotes K48-linked polyubiquitination of HNF4α, leading to the inhibition of HBV replication","authors":"Atsuya Yamashita , Hirotake Kasai , Shinya Maekawa , Tomohisa Tanaka , Yasunori Akaike , Akihide Ryo , Nobuyuki Enomoto , Kohji Moriishi","doi":"10.1016/j.antiviral.2024.106027","DOIUrl":"10.1016/j.antiviral.2024.106027","url":null,"abstract":"<div><div>The current antiviral agents for the treatment of chronic infection with hepatitis B virus (HBV) do not completely remove covalently closed circular DNA (cccDNA) and integrated viral DNA fragments from patients. Berberine is an isoquinoline alkaloid extracted from various plants and has been reported to inhibit the replication of various types of DNA. In this study, we tested the effects of berberine and its derivatives on HBV infection. Berberine inhibited viral core promoter activity at the highest level among the compounds tested and suppressed HBV production and cccDNA synthesis in primary human hepatocytes and HBV-infected HepG2-NTCP cells at an EC<sub>50</sub> value of 3.6 μM and a CC<sub>50</sub> value of over 240.0 μM. Compared with other viral promoter activities, berberine treatment potently downregulated core promoter activity and reduced protein levels, but not RNA levels, of hepatic nuclear factor 4α (HNF4α), which primarily enhances enhancer II/core promoter activity. Furthermore, berberine treatment enhanced K<sup>48</sup>-linked, but not K<sup>63</sup>-linked, polyubiquitination and subsequent proteasome-dependent degradation of HNF4α. These results suggest that berberine enhances the polyubiquitination- and proteasome-dependent degradation of HNF4α and then inhibits HBV replication via the suppression of core promoter activity. The development of antiviral agents based on berberine may contribute to the amelioration of HBV-related disorders, regardless of the presence of residual cccDNA or integrated viral DNA fragments.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"232 ","pages":"Article 106027"},"PeriodicalIF":4.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Replication capacity and susceptibility of nirmatrelvir-resistant mutants to next-generation Mpro inhibitors in a SARS-CoV-2 replicon system 在 SARS-CoV-2 复制子系统中 Nirmatrelvir 抗性突变体的复制能力和对新一代 Mpro 抑制剂的敏感性。

IF 4.5 2区医学

Antiviral research Pub Date : 2024-11-01 DOI: 10.1016/j.antiviral.2024.106022

Chieh-Wen Lo , Omri Kariv , Chenzhou Hao , Karen Anbro Gammeltoft , Jens Bukh , Judith Gottwein , Michael Westberg , Michael Z. Lin , Shirit Einav

{"title":"Replication capacity and susceptibility of nirmatrelvir-resistant mutants to next-generation Mpro inhibitors in a SARS-CoV-2 replicon system","authors":"Chieh-Wen Lo , Omri Kariv , Chenzhou Hao , Karen Anbro Gammeltoft , Jens Bukh , Judith Gottwein , Michael Westberg , Michael Z. Lin , Shirit Einav","doi":"10.1016/j.antiviral.2024.106022","DOIUrl":"10.1016/j.antiviral.2024.106022","url":null,"abstract":"<div><div>There is an ongoing need to expand the anti-SARS-CoV-2 armamentarium to include agents capable of suppressing replication of drug-resistant mutants emerging during monotherapy with approved direct-acting antivirals. Using a subgenomic SARS-CoV-2 replicon system, we studied the RNA replication capacity of nirmatrelvir (NTV)-resistant mutants and their susceptibility to next-generation Mpro inhibitors, including ibuzatrelvir (ITV), ensitrelvir (ETV), and ML2006a4. Our findings revealed that E166V Mpro mutants reduced viral RNA replication, whereas other Mpro mutations retained or increased the replication capacity, suggesting the potential of the latter to dominate under NTV selective pressure. Except for having an advantage against E166A mutants, ITV largely showed the same mutational sensitivity as NTV. ETV was more effective than NTV against E166V mutants but less effective against S144A, E166A, and L167F mutants. ML2006a4 demonstrated the most effective suppression across most mutants (S144A, E166V, S144A + L50F, E166 A/V + L50F, L167F + L50F, and E166A + L167F + L50F). Thus, ML2006a4 represents an attractive investigational candidate against clinically relevant NTV-resistant SARS-CoV-2 mutants.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 106022"},"PeriodicalIF":4.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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