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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 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-12 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

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.

第 37 届国际抗病毒研究大会(ICAR)于 2024 年 5 月 20-24 日在澳大利亚黄金海岸举行。2024 年国际抗病毒研究大会有超过 75 个专题报告、两场海报展览和特别活动,其中包括专门为受训人员和早期职业科学家量身定制的活动。会议是交流前沿研究的平台,演讲和讨论内容涉及新型抗病毒化合物、疫苗开发、临床试验和治疗进展。从抗病毒药物开发的最新突破到应对新出现病毒威胁的创新战略,会议涵盖了抗病毒科学领域的所有主题。主题演讲深入探讨了医疗对策开发和使用的两个基本领域,包括病毒在人与动物界面的出现以及将抗病毒药物应用于临床的实际考虑因素。其他会议还讨论了大流行后的各种及时话题,如寻找广谱抗病毒药物、联合疗法、大流行准备、药物发现中的硅学工具和人工智能应用、病毒球等。在此,我们总结了 2024 年 ICAR 的所有演讲和特别会议,并介绍了将于 2025 年 3 月 17-21 日在美国拉斯维加斯举行的第 38 届 ICAR。
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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 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-11 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

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.

宫颈癌通常是由 HPV16 或 HPV18 等高危人乳头瘤病毒(HPV)感染引起的,它仍然是癌症相关死亡的主要原因。约 90% 的宫颈癌患者体内都发现了 HPV16,它携带的关键致癌相关基因(E6、E7、E2、E5)和上游调控区(URR)有助于癌症的发展。本研究采用一种名为 SONC103 的重组单纯疱疹病毒 1 型(HSV-1)与 CRISPR/Cas9 基因编辑系统相结合的新方法。目的是靶向破坏宫颈癌细胞中整合的HPV16基因。结果表明,SONC103 能够特异性地有效敲除 HPV16 致癌基因,从而减少细胞增殖并促进细胞凋亡。分析进一步揭示了感染细胞染色体中HPV16 DNA探针的缺失、与肿瘤凋亡相关的细胞过程的显著调节、E6/E7肿瘤蛋白的下调以及肿瘤抑制蛋白P53和pRB的增加。值得注意的是,SONC103 在小鼠异种移植宫颈癌模型中表现出对肿瘤生长的显著抑制作用。这项研究展示了重组溶瘤HSV-1病毒(SONC103)通过靶向癌基因和促进溶瘤来抗击HPV16阳性宫颈癌的潜力。
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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 Q1 PHARMACOLOGY & PHARMACY 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
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.
伪狂犬病毒(PRV)是阿尔法疱疹病毒亚科的成员,也是奥杰斯基病的致病病原体,其宿主范围很广,包括家畜和野生动物。据报道,PRV 是 2021 年急性脑炎患者的病原体,这表明 PRV 可能是一种新型的动物源病毒,具有人畜共患的外溢性和传播潜力。管理当前在猪中流行的 PRV,并为未来在包括人类在内的其他物种中流行做好准备。基础技术对于获得预防和治疗 PRV 的知识至关重要。本研究分离了 PRV CD22 株,系统进化分析表明 PRV CD22 属于目前中国流行的毒株。PRV CD22对小鼠和仔猪的体内致死率很高。此外,基于PRV CD22基因组DNA fosmid文库,构建了快速高效的PRV重组系统。利用该系统,重组 PRV 株系表达了工程标记蛋白,可用于小鼠模型中病毒感染的可视化。我们的研究能够产生可用于下游治疗分析的 PRV。一旦获得实验或监测样本,就可以根据我们的研究高效地生成和处理 PRV。
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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 Q1 PHARMACOLOGY & PHARMACY 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

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.

雷米替韦(RDV,Veklury®)是美国食品及药物管理局批准的第一种治疗 COVID-19 的抗病毒药物。它是一种核苷酸类似物(NA),带有核糖上的 1'-cyano (1'-CN) 基团和假腺嘌呤核碱基,其对作用模式(MoA)的贡献尚不清楚。在这里,我们通过使用 RDV-TP 类似物来剖析这些独立的贡献。我们发现,1'-CN 基团直接导致 SARS-CoV-2 复制/转录复合体(RTC)的瞬时停滞,而核碱基则对这种停滞的强度起作用。相反,RNA 延伸试验表明,1'-CN 基团在保真度方面起作用,RDV-TP 可以作为 GTP 类似物结合,尽管效率较低。然而,对用 RDV 处理过的细胞中的病毒 RNA 进行深度测序并不能确定病毒聚合酶会产生诱变作用。我们观察到,一旦添加到 RNA 的 3' 端,RDV-MP 对切除很敏感,其 1'-CN 基团不会影响 nsp14 介导的切除。在 nsp12 序列中,可以筛选出携带 S759A 和 A777S 两种突变的抗 RDV >14 倍的 SARS-CoV-2 分离物。这两种突变既能使 nsp12 对 RDV-TP 的辨别能力超过 ATP,又能使 RNA 合成过程停滞,从而为切除修复留出更多时间,并有可能降低 RDV 的效率。我们的结论是,RDV 具有多面性。它减缓或阻滞了整个 RNA 合成,但能从引物链中有效修复,而一旦进入模板,通读抑制又会增加这种效果。它的有效加入可能会破坏前病毒 RNA,从而可能干扰病毒生命周期中的下游功能。
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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 Q1 PHARMACOLOGY & PHARMACY 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
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 EC50 value of 3.6 μM and a CC50 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 K48-linked, but not K63-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.
目前用于治疗慢性乙型肝炎病毒(HBV)感染的抗病毒药物并不能完全清除患者体内的共价闭合环状 DNA(cccDNA)和整合病毒 DNA 片段。小檗碱是从多种植物中提取的一种异喹啉生物碱,据报道可抑制多种类型 DNA 的复制。在这项研究中,我们测试了小檗碱及其衍生物对 HBV 感染的影响。在所测试的化合物中,小檗碱抑制病毒核心启动子活性的水平最高,能抑制原代人类肝细胞和受 HBV 感染的 HepG2-NTCP 细胞中 HBV 的产生和 cccDNA 的合成,EC50 值为 3.6 μM,CC50 值超过 240.0 μM。与其他病毒启动子活性相比,小檗碱处理能有效下调核心启动子活性,降低肝核因子 4α (HNF4α)的蛋白水平,但不降低 RNA 水平,而 HNF4α 主要增强 II/核心启动子活性。此外,小檗碱处理增强了与 K48 链接的多泛素化,而不是与 K63 链接的多泛素化,以及随后蛋白酶体依赖性降解 HNF4α。这些结果表明,小檗碱能增强 HNF4α 的多泛素化和蛋白酶体依赖性降解,然后通过抑制核心启动子的活性抑制 HBV 复制。无论是否存在残留的cccDNA或整合的病毒DNA片段,开发基于小檗碱的抗病毒药物都可能有助于改善与HBV相关的疾病。
{"title":"Berberine promotes K48-linked polyubiquitination of HNF4α, leading to the inhibition of HBV replication","authors":"Atsuya Yamashita ,&nbsp;Hirotake Kasai ,&nbsp;Shinya Maekawa ,&nbsp;Tomohisa Tanaka ,&nbsp;Yasunori Akaike ,&nbsp;Akihide Ryo ,&nbsp;Nobuyuki Enomoto ,&nbsp;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 Q1 PHARMACOLOGY & PHARMACY 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
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.
目前需要扩大抗 SARS-CoV-2 的药物范围,以包括能够抑制在使用已批准的直接作用抗病毒药物进行单药治疗期间出现的耐药突变体复制的药物。我们利用亚基因组 SARS-CoV-2 复制子系统研究了耐药突变体 nirmatrelvir (NTV) 的 RNA 复制能力及其对新一代 Mpro 抑制剂(包括 ibuzatrelvir (ITV)、ensitrelvir (ETV) 和 ML2006a4)的敏感性。我们的研究结果表明,E166V Mpro 突变体降低了病毒 RNA 复制能力,而其他 Mpro 突变体则保持或提高了复制能力,这表明后者有可能在 NTV 选择性压力下占据主导地位。除了对 E166A 突变体有优势外,ITV 在很大程度上表现出与 NTV 相同的突变敏感性。ETV 对 E166V 突变体比 NTV 更有效,但对 S144A、E166A 和 L167F 突变体的效果较差。ML2006a4 对大多数突变体(S144A、E166V、S144A+L50F、E166A/V+L50F、L167F+L50F 和 E166A+L167F+L50F)的抑制效果最好。因此,ML2006a4 是一种极具吸引力的候选药物,可用于抗击临床相关的 NTV 抗性 SARS-CoV-2 突变体。
{"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 ,&nbsp;Omri Kariv ,&nbsp;Chenzhou Hao ,&nbsp;Karen Anbro Gammeltoft ,&nbsp;Jens Bukh ,&nbsp;Judith Gottwein ,&nbsp;Michael Westberg ,&nbsp;Michael Z. Lin ,&nbsp;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}
引用次数: 0
Novel intercellular spread mode of respiratory syncytial virus contributes to neutralization escape 呼吸道合胞病毒的新型细胞间传播模式有助于中和逃逸。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-01 DOI: 10.1016/j.antiviral.2024.106023
Wei Zhang , Xue Lin , Zhi-Yong Li , Lu-Jing Zhang , Li Chen , Yong-Peng Sun , Jun-Yu Si , Min Zhao , Guang-Hua Wu , Lu-Ting Zhan , Kun-Yu Yang , Rui-Luan You , Ying-Bin Wang , Ning-Shao Xia , Zi-Zheng Zheng
Developing widely used respiratory syncytial virus (RSV) vaccines remains a significant challenge, despite the recent authorization of two pre-F vaccines for elderly adults. Previous reports have suggested that even when vaccine-induced immunity generates high titers of potent neutralizing antibodies targeting the pre-F protein, it may not fully inhibit breakthrough of RSV infections. This incomplete inhibition of RSV breakthrough infections can lead to an increased risk of enhanced respiratory disease (ERD) in vaccinated individuals. The reasons why potent neutralizing antibodies cannot fully prevent RSV breakthrough infections are not yet clear. In an attempt to explain this phenomenon, we investigated the effect of potent neutralizing antibodies on the intercellular spread of RSV. Our findings indicated that a specific titer of potent neutralizing antibodies, such as 5C4, could block certain modes of intercellular spread, such as the diffusion of cell-free virions and the delivery of virions through filopodia. However, these antibodies did not fully inhibit the entire process of intercellular spread. Through the use of super-resolution imaging techniques, we observed a novel and efficient spread mode called the transition of viral materials through intercellular nanotubes (TVMIN), independent of virions and insensitive to the presence of antibodies. TVMIN allowed RSV-infected cells to directly transfer viral materials to neighboring cells via intercellular nanotubes that are rich in microfilaments. TVMIN began as early as 5 h post-infection (h.p.i.) and rapidly initiated infection in recipient cells. Our data provided new insights into the intercellular spread of RSV and might help explain the occurrence of breakthrough infections.
尽管最近批准了两种针对老年人的前 F 疫苗,但开发广泛使用的呼吸道合胞病毒(RSV)疫苗仍是一项重大挑战。以前的报告表明,即使疫苗诱导免疫产生了针对前 F 蛋白的高滴度强效中和抗体,也可能无法完全抑制 RSV 的突破性感染。这种对 RSV 突破性感染的不完全抑制会导致接种疫苗的人患呼吸道疾病(ERD)的风险增加。强效中和抗体不能完全阻止 RSV 突破性感染的原因尚不清楚。为了解释这一现象,我们研究了强效中和抗体对 RSV 细胞间传播的影响。我们的研究结果表明,特定滴度的强效中和抗体(如 5C4)可以阻止某些细胞间传播方式,如无细胞病毒的扩散和病毒通过丝状体的传递。然而,这些抗体并不能完全抑制整个细胞间传播过程。通过使用超分辨率成像技术,我们观察到了一种新颖高效的传播模式,即病毒物质通过细胞间纳米管的过渡(TVMIN),它独立于病毒,对抗体的存在不敏感。TVMIN允许RSV感染细胞通过富含微丝的细胞间纳米管直接将病毒物质转移到邻近细胞。TVMIN 早在感染后 5 小时(h.p.i.)就开始发挥作用,并迅速引发受体细胞感染。我们的数据为研究 RSV 的细胞间传播提供了新的视角,可能有助于解释突破性感染的发生。
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引用次数: 0
Corrigendum to “Discovery of ZFD-10 of a pyridazino[4,5-b]indol-4(5H)-one derivative as an anti-ZIKV agent and a ZIKV NS5 RdRp inhibitor” [Antivir. Res. 214 (2023) 105607] 对 "发现哒嗪并[4,5-b]吲哚-4(5H)-酮衍生物 ZFD-10 作为抗 ZIKV 药物和 ZIKV NS5 RdRp 抑制剂 "的更正[Antivir. Res. 214 (2023) 105607]。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-01 DOI: 10.1016/j.antiviral.2024.106025
Guang-Feng Zhou , Weiyi Qian , Feng Li , Ren-Hua Yang , Na Wang , Chang-Bo Zheng , Chun-Yan Li , Xue-Rong Gu , Liu-Meng Yang , Jinsong Liu , Si-Dong Xiong , Guo-Chun Zhou , Yong-Tang Zheng
{"title":"Corrigendum to “Discovery of ZFD-10 of a pyridazino[4,5-b]indol-4(5H)-one derivative as an anti-ZIKV agent and a ZIKV NS5 RdRp inhibitor” [Antivir. Res. 214 (2023) 105607]","authors":"Guang-Feng Zhou ,&nbsp;Weiyi Qian ,&nbsp;Feng Li ,&nbsp;Ren-Hua Yang ,&nbsp;Na Wang ,&nbsp;Chang-Bo Zheng ,&nbsp;Chun-Yan Li ,&nbsp;Xue-Rong Gu ,&nbsp;Liu-Meng Yang ,&nbsp;Jinsong Liu ,&nbsp;Si-Dong Xiong ,&nbsp;Guo-Chun Zhou ,&nbsp;Yong-Tang Zheng","doi":"10.1016/j.antiviral.2024.106025","DOIUrl":"10.1016/j.antiviral.2024.106025","url":null,"abstract":"","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 106025"},"PeriodicalIF":4.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543352","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
Oral 3CL protease inhibitor ensitrelvir suppressed SARS-CoV-2 shedding and infection in a hamster aerosol transmission model 口服 3CL 蛋白酶抑制剂 ensitrelvir 可抑制仓鼠气溶胶传播模型中 SARS-CoV-2 的脱落和感染。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-29 DOI: 10.1016/j.antiviral.2024.106026
Masaaki Nakashima , Haruaki Nobori , Takayuki Kuroda , Alice Shimba , Satoshi Miyagawa , Akane Hayashi , Kazumi Matsumoto , Mei Yoshida , Kaoru Baba , Teruhisa Kato , Keita Fukao
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) remain a major global health challenge, with aerosol transmission being the primary route of spread. The use of antivirals as medical countermeasures to control SARS-CoV-2 transmission and spread is promising but remains to be clarified. The current study established and used an in vivo hamster aerosol transmission model system to evaluate the efficacy of the protease inhibitor ensitrelvir to prevent the spread of SARS-CoV-2. Male Index Syrian hamsters were intranasally infected with SARS-CoV-2, paired with naïve Contact hamsters, and co-housed for 12 h under conditions to allow for only aerosol transmission. The Index hamsters were treated three times with ensitrelvir starting 8 h post infection, or the Contact hamsters were treated once with ensitrelvir 12 h prior to co-housing. Viral infection and transmission were monitored by evaluating nasal lavage fluid, lung tissues, and body and lung weights. Post-infection administration of ensitrelvir to Index hamsters suppressed virus shedding in a dose-dependent manner. Pre-exposure administration of 750 mg/kg ensitrelvir to naïve Contact hamsters also protected against aerosol SARS-CoV-2 infection in a dose-dependent manner. Furthermore, pre-exposure treatment of 750 mg/kg ensitrelvir supressed body weight loss and lung weight increase of aerosol infected hamsters compared to vehicle-treated hamsters. These findings suggest that ensitrelvir may prevent SARS-CoV-2 spread when administered to infected patients and may prevent or limit SARS-CoV-2 infection when prophylactically administered to non-infected individuals. Both approaches may help protect at-risk individuals, such as family members living with SARS-CoV-2-infected patients.
严重急性呼吸系统综合症冠状病毒 2(SARS-CoV-2)和冠状病毒病 2019(COVID-19)仍然是全球健康面临的一大挑战,气溶胶传播是其主要传播途径。使用抗病毒药物作为医疗对策来控制 SARS-CoV-2 的传播和扩散前景广阔,但仍有待明确。本研究建立并使用了一个体内仓鼠气溶胶传播模型系统,以评估蛋白酶抑制剂 ensitrelvir 预防 SARS-CoV-2 传播的效果。雄性 Index 叙利亚仓鼠经鼻内感染 SARS-CoV-2,与天真接触仓鼠配对,在仅允许气溶胶传播的条件下共同饲养 12 小时。指数仓鼠在感染后 8 小时开始接受三次恩西特韦治疗,或接触仓鼠在共同饲养前 12 小时接受一次恩西特韦治疗。通过评估鼻腔灌洗液、肺组织以及身体和肺的重量来监测病毒感染和传播。疫点仓鼠感染后服用安赛列韦可抑制病毒脱落,其效果与剂量有关。天真的接触仓鼠在接触前服用 750 毫克/千克的恩西特韦,也能以剂量依赖的方式防止气溶胶 SARS-CoV-2 感染。此外,与用药物治疗的仓鼠相比,暴露前服用750毫克/千克恩西特韦可抑制气溶胶感染仓鼠的体重下降和肺重量增加。这些研究结果表明,对感染患者施用恩西特韦可防止 SARS-CoV-2 的传播,对非感染者预防性施用恩西特韦可防止或限制 SARS-CoV-2 的感染。这两种方法都有助于保护高危人群,如与 SARS-CoV-2 感染者生活在一起的家庭成员。
{"title":"Oral 3CL protease inhibitor ensitrelvir suppressed SARS-CoV-2 shedding and infection in a hamster aerosol transmission model","authors":"Masaaki Nakashima ,&nbsp;Haruaki Nobori ,&nbsp;Takayuki Kuroda ,&nbsp;Alice Shimba ,&nbsp;Satoshi Miyagawa ,&nbsp;Akane Hayashi ,&nbsp;Kazumi Matsumoto ,&nbsp;Mei Yoshida ,&nbsp;Kaoru Baba ,&nbsp;Teruhisa Kato ,&nbsp;Keita Fukao","doi":"10.1016/j.antiviral.2024.106026","DOIUrl":"10.1016/j.antiviral.2024.106026","url":null,"abstract":"<div><div>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) remain a major global health challenge, with aerosol transmission being the primary route of spread. The use of antivirals as medical countermeasures to control SARS-CoV-2 transmission and spread is promising but remains to be clarified. The current study established and used an <em>in vivo</em> hamster aerosol transmission model system to evaluate the efficacy of the protease inhibitor ensitrelvir to prevent the spread of SARS-CoV-2. Male Index Syrian hamsters were intranasally infected with SARS-CoV-2, paired with naïve Contact hamsters, and co-housed for 12 h under conditions to allow for only aerosol transmission. The Index hamsters were treated three times with ensitrelvir starting 8 h post infection, or the Contact hamsters were treated once with ensitrelvir 12 h prior to co-housing. Viral infection and transmission were monitored by evaluating nasal lavage fluid, lung tissues, and body and lung weights. Post-infection administration of ensitrelvir to Index hamsters suppressed virus shedding in a dose-dependent manner. Pre-exposure administration of 750 mg/kg ensitrelvir to naïve Contact hamsters also protected against aerosol SARS-CoV-2 infection in a dose-dependent manner. Furthermore, pre-exposure treatment of 750 mg/kg ensitrelvir supressed body weight loss and lung weight increase of aerosol infected hamsters compared to vehicle-treated hamsters. These findings suggest that ensitrelvir may prevent SARS-CoV-2 spread when administered to infected patients and may prevent or limit SARS-CoV-2 infection when prophylactically administered to non-infected individuals. Both approaches may help protect at-risk individuals, such as family members living with SARS-CoV-2-infected patients.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"232 ","pages":"Article 106026"},"PeriodicalIF":4.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543353","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
SiRNAs as antiviral drugs – Current status, therapeutic potential and challenges 作为抗病毒药物的 SiRNA - 现状、治疗潜力和挑战。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-23 DOI: 10.1016/j.antiviral.2024.106024
Trairong Chokwassanasakulkit , Victor Baba Oti , Adi Idris , Nigel AJ. McMillan
Traditionally, antiviral drugs target viral enzymes and or structural proteins, identified through large drug screens or rational drug design. The screening, chemical optimisation, small animal toxicity studies and clinical trials mean time to market is long for a new compound, and in the event of a novel virus or pandemic, weeks, and months matter. Small interfering RNAs (siRNAs) as a gene silencing platform is an alluring alternative. SiRNAs are now approved for use in the clinic to treat a range of diseases, are cost effective, scalable, and can be easily programmed to target any viral target in a matter of days. Despite the large number of preclinical studies that clearly show siRNAs are highly effective antivirals this has not translated into clinical success with no products on the market. This review provides a comprehensive overview of both the clinical and preclinical work in this area and outlines the challenges the field faces going forward that need to be addressed in order to see siRNA antivirals become a clinical reality.
传统上,抗病毒药物以病毒酶和结构蛋白为目标,通过大型药物筛选或合理药物设计确定。筛选、化学优化、小动物毒性研究和临床试验意味着新化合物的上市时间很长,如果出现新型病毒或大流行病,则需要数周甚至数月的时间。作为基因沉默平台的小干扰 RNA(siRNA)是一种诱人的选择。目前,SiRNA 已被批准用于临床治疗一系列疾病,其成本效益高、可扩展性强,并可在数天内轻松编程为针对任何病毒靶点的程序。尽管大量临床前研究清楚地表明 siRNA 是高效的抗病毒药物,但这并没有转化为临床上的成功,目前市场上还没有相关产品。本综述全面概述了这一领域的临床和临床前研究工作,并概述了该领域未来面临的挑战,这些挑战亟待解决,才能让 siRNA 抗病毒药物成为临床现实。
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Antiviral research
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