Pub Date : 2024-06-04DOI: 10.1016/j.antiviral.2024.105923
Virginia Aida-Ficken , Jamie A. Kelly , Payel Chatterjee , M. Harley Jenks , Laura K. McMullan , César G. Albariño , Joel M. Montgomery , Katherine L. Seley-Radtke , Christina F. Spiropoulou , Mike Flint
There are no approved vaccines or therapeutics for Lassa virus (LASV) infections. To identify compounds with anti-LASV activity, we conducted a cell-based screening campaign at biosafety level 4 and tested almost 60,000 compounds for activity against an infectious reporter LASV. Hits from this screen included several structurally related macrocycles. The most potent, Mac128, had a sub-micromolar EC50 against the reporter virus, inhibited wild-type clade IV LASV, and reduced viral titers by 4 orders of magnitude. Mechanistic studies suggested that Mac128 inhibited viral replication at the level of the polymerase.
{"title":"Identification of a macrocyclic compound targeting the lassa virus polymerase","authors":"Virginia Aida-Ficken , Jamie A. Kelly , Payel Chatterjee , M. Harley Jenks , Laura K. McMullan , César G. Albariño , Joel M. Montgomery , Katherine L. Seley-Radtke , Christina F. Spiropoulou , Mike Flint","doi":"10.1016/j.antiviral.2024.105923","DOIUrl":"10.1016/j.antiviral.2024.105923","url":null,"abstract":"<div><p>There are no approved vaccines or therapeutics for Lassa virus (LASV) infections. To identify compounds with anti-LASV activity, we conducted a cell-based screening campaign at biosafety level 4 and tested almost 60,000 compounds for activity against an infectious reporter LASV. Hits from this screen included several structurally related macrocycles. The most potent, Mac128, had a sub-micromolar EC<sub>50</sub> against the reporter virus, inhibited wild-type clade IV LASV, and reduced viral titers by 4 orders of magnitude. Mechanistic studies suggested that Mac128 inhibited viral replication at the level of the polymerase.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":null,"pages":null},"PeriodicalIF":7.6,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0166354224001323/pdfft?md5=e57c3d54395b9f15fe54fae4c4bf6a42&pid=1-s2.0-S0166354224001323-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141282881","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}
Pub Date : 2024-05-31DOI: 10.1016/j.antiviral.2024.105922
Michelle Jagst , André Gömer , Daniel Todt , Eike Steinmann
Hepatitis E is an underestimated disease, leading to estimated 20 million infections and up to 70,000 deaths annually. Infections are mostly asymptomatic, but can reach mortality rates up to 25% in pregnant women or become chronic in immunocompromised patients. Hepatitis E virus (HEV) infection have been associated with a range of extrahepatic manifestations, including a spectrum of neurological symptoms. Current therapy options are limited to non-specific antivirals like ribavirin, but recently, repurposed viral polymerase inhibitors like sofosbuvir and NITD008 were described to inhibit HEV replication. Here, we evaluated the efficacy of these drugs in various neuronal-derived cell lines to determine their potency outside the liver. Our findings indicate that both drugs, especially sofosbuvir, exhibited reduced efficacy in neuronal cells compared to hepatic cells. These results should be taken into account in the development of direct-acting antivirals for HEV and their potency at extrahepatic replication sites.
戊型肝炎是一种被低估的疾病,估计每年导致 2 千万人感染,多达 7 万人死亡。感染者大多无症状,但孕妇的死亡率可高达 25%,免疫力低下的患者则会转为慢性感染。戊型肝炎病毒(HEV)感染与一系列肝外表现有关,包括一系列神经系统症状。目前的治疗方法仅限于利巴韦林等非特异性抗病毒药物,但最近出现了索非布韦和 NITD008 等重新设计用途的病毒聚合酶抑制剂来抑制戊型肝炎病毒的复制。在这里,我们评估了这些药物在各种神经元衍生细胞系中的疗效,以确定它们在肝脏外的效力。我们的研究结果表明,与肝细胞相比,这两种药物(尤其是索非布韦)在神经元细胞中的疗效都有所下降。在开发针对 HEV 的直接作用抗病毒药物及其在肝外复制位点的效力时应考虑到这些结果。
{"title":"Performance of sofosbuvir and NITD008 in extrahepatic neuronal cells against HEV","authors":"Michelle Jagst , André Gömer , Daniel Todt , Eike Steinmann","doi":"10.1016/j.antiviral.2024.105922","DOIUrl":"10.1016/j.antiviral.2024.105922","url":null,"abstract":"<div><p>Hepatitis E is an underestimated disease, leading to estimated 20 million infections and up to 70,000 deaths annually. Infections are mostly asymptomatic, but can reach mortality rates up to 25% in pregnant women or become chronic in immunocompromised patients. Hepatitis E virus (HEV) infection have been associated with a range of extrahepatic manifestations, including a spectrum of neurological symptoms. Current therapy options are limited to non-specific antivirals like ribavirin, but recently, repurposed viral polymerase inhibitors like sofosbuvir and NITD008 were described to inhibit HEV replication. Here, we evaluated the efficacy of these drugs in various neuronal-derived cell lines to determine their potency outside the liver. Our findings indicate that both drugs, especially sofosbuvir, exhibited reduced efficacy in neuronal cells compared to hepatic cells. These results should be taken into account in the development of direct-acting antivirals for HEV and their potency at extrahepatic replication sites.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":null,"pages":null},"PeriodicalIF":7.6,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0166354224001311/pdfft?md5=34bb04514ebd5d14b660b812e4e2d407&pid=1-s2.0-S0166354224001311-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199307","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}
Pub Date : 2024-05-31DOI: 10.1016/j.antiviral.2024.105921
Benjamin Van Loy, Annelies Stevaert, Lieve Naesens
The SARS-CoV-2 pandemic has bolstered unprecedented research efforts to better understand the pathogenesis of coronavirus (CoV) infections and develop effective therapeutics. We here focus on non-structural protein nsp15, a hexameric component of the viral replication-transcription complex (RTC). Nsp15 possesses uridine-specific endoribonuclease (EndoU) activity for which some specific cleavage sites were recently identified in viral RNA. By preventing accumulation of viral dsRNA, EndoU helps the virus to evade RNA sensors of the innate immune response. The immune-evading property of nsp15 was firmly established in several CoV animal models and makes it a pertinent target for antiviral therapy. The search for nsp15 inhibitors typically proceeds via compound screenings and is aided by the rapidly evolving insight in the protein structure of nsp15. In this overview, we broadly cover this fascinating protein, starting with its structure, biochemical properties and functions in CoV immune evasion. Next, we summarize the reported studies in which compound screening or a more rational method was used to identify suitable leads for nsp15 inhibitor development. In this way, we hope to raise awareness on the relevance and druggability of this unique CoV protein.
{"title":"The coronavirus nsp15 endoribonuclease: A puzzling protein and pertinent antiviral drug target","authors":"Benjamin Van Loy, Annelies Stevaert, Lieve Naesens","doi":"10.1016/j.antiviral.2024.105921","DOIUrl":"10.1016/j.antiviral.2024.105921","url":null,"abstract":"<div><p>The SARS-CoV-2 pandemic has bolstered unprecedented research efforts to better understand the pathogenesis of coronavirus (CoV) infections and develop effective therapeutics. We here focus on non-structural protein nsp15, a hexameric component of the viral replication-transcription complex (RTC). Nsp15 possesses uridine-specific endoribonuclease (EndoU) activity for which some specific cleavage sites were recently identified in viral RNA. By preventing accumulation of viral dsRNA, EndoU helps the virus to evade RNA sensors of the innate immune response. The immune-evading property of nsp15 was firmly established in several CoV animal models and makes it a pertinent target for antiviral therapy. The search for nsp15 inhibitors typically proceeds via compound screenings and is aided by the rapidly evolving insight in the protein structure of nsp15. In this overview, we broadly cover this fascinating protein, starting with its structure, biochemical properties and functions in CoV immune evasion. Next, we summarize the reported studies in which compound screening or a more rational method was used to identify suitable leads for nsp15 inhibitor development. In this way, we hope to raise awareness on the relevance and druggability of this unique CoV protein.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":null,"pages":null},"PeriodicalIF":7.6,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199309","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}
Pub Date : 2024-05-29DOI: 10.1016/j.antiviral.2024.105920
Uyen Nguyen Phuong Le , Yu-Jen Chang , Chih-Hao Lu , Yeh Chen , Wen-Chi Su , Shao-Ting Chao , Lia A. Baltina , Svetlana F. Petrova , Sin-Rong Li , Mien-Chie Hung , Michael M.C. Lai , Lidia A. Baltina , Cheng-Wen Lin
COVID-19 pandemic is predominantly caused by SARS-CoV-2, with its main protease, Mpro, playing a pivotal role in viral replication and serving as a potential target for inhibiting different variants. In this study, potent Mpro inhibitors were identified from glycyrrhizic acid (GL) derivatives with amino acid methyl/ethyl esters. Out of the 17 derivatives semisynthesized, Compounds 2, 6, 9, and 15, with methionine methyl esters, D-tyrosine methyl esters, glutamic acid methyl esters, and methionines in the carbohydrate moiety, respectively, significantly inhibited wild-type SARS-CoV-2 Mpro-mediated proteolysis, with IC50 values ranging from 0.06 μM to 0.84 μM. They also demonstrated efficacy in inhibiting trans-cleavage by mutant Mpro variants (Mpro_P132H, Mpro_E166V, Mpro_P168A, Mpro_Q189I), with IC50 values ranging from 0.05 to 0.92 μM, surpassing nirmatrelvir (IC50: 1.17–152.9 μM). Molecular modeling revealed stronger interactions with Valine166 in the structural complex of Mpro_E166V with the compounds compared to nirmatrelvir. Moreover, these compounds efficiently inhibited the post-entry viral processes of wild-type SARS-CoV-2 single-round infectious particles (SRIPs), mitigating viral cytopathic effects and reducing replicon-driven GFP reporter signals, as well as in vitro infectivity of wild-type, Mpro_E166V, and Mpro_Q189I SRIPs, with EC50 values ranging from 0.02 to 0.53 μM. However, nirmatrelvir showed a significant decrease in inhibiting the replication of mutant SARS-CoV-2 SRIPs carrying Mpro_E166V (EC50: >20 μM) and Mpro_Q189I (EC50: 13.2 μM) compared to wild-type SRIPs (EC50: 0.06 μM). Overall, this study identifies four GL derivatives as promising lead compounds for developing treatments against various SARS-CoV-2 strains, including Omicron, and nirmatrelvir-resistant variants.
{"title":"Glycyrrhizic acid conjugates with amino acid methyl esters target the main protease, exhibiting antiviral activity against wild-type and nirmatrelvir-resistant SARS-CoV-2 variants","authors":"Uyen Nguyen Phuong Le , Yu-Jen Chang , Chih-Hao Lu , Yeh Chen , Wen-Chi Su , Shao-Ting Chao , Lia A. Baltina , Svetlana F. Petrova , Sin-Rong Li , Mien-Chie Hung , Michael M.C. Lai , Lidia A. Baltina , Cheng-Wen Lin","doi":"10.1016/j.antiviral.2024.105920","DOIUrl":"10.1016/j.antiviral.2024.105920","url":null,"abstract":"<div><p>COVID-19 pandemic is predominantly caused by SARS-CoV-2, with its main protease, Mpro, playing a pivotal role in viral replication and serving as a potential target for inhibiting different variants. In this study, potent Mpro inhibitors were identified from glycyrrhizic acid (GL) derivatives with amino acid methyl/ethyl esters. Out of the 17 derivatives semisynthesized, Compounds <strong>2</strong>, <strong>6</strong>, <strong>9</strong>, and <strong>15</strong>, with methionine methyl esters, D-tyrosine methyl esters, glutamic acid methyl esters, and methionines in the carbohydrate moiety, respectively, significantly inhibited wild-type SARS-CoV-2 Mpro-mediated proteolysis, with IC50 values ranging from 0.06 μM to 0.84 μM. They also demonstrated efficacy in inhibiting trans-cleavage by mutant Mpro variants (Mpro_P132H, Mpro_E166V, Mpro_P168A, Mpro_Q189I), with IC50 values ranging from 0.05 to 0.92 μM, surpassing nirmatrelvir (IC50: 1.17–152.9 μM). Molecular modeling revealed stronger interactions with Valine166 in the structural complex of Mpro_E166V with the compounds compared to nirmatrelvir. Moreover, these compounds efficiently inhibited the post-entry viral processes of wild-type SARS-CoV-2 single-round infectious particles (SRIPs), mitigating viral cytopathic effects and reducing replicon-driven GFP reporter signals, as well as in vitro infectivity of wild-type, Mpro_E166V, and Mpro_Q189I SRIPs, with EC50 values ranging from 0.02 to 0.53 μM. However, nirmatrelvir showed a significant decrease in inhibiting the replication of mutant SARS-CoV-2 SRIPs carrying Mpro_E166V (EC50: >20 μM) and Mpro_Q189I (EC50: 13.2 μM) compared to wild-type SRIPs (EC50: 0.06 μM). Overall, this study identifies four GL derivatives as promising lead compounds for developing treatments against various SARS-CoV-2 strains, including Omicron, and nirmatrelvir-resistant variants.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":null,"pages":null},"PeriodicalIF":7.6,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141183623","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}
Pub Date : 2024-05-23DOI: 10.1016/j.antiviral.2024.105918
Diana A. Franco-May , Jesús Gómez-Carballo , Gisela Barrera-Badillo , María N. Cruz-Ortíz , Tatiana E. Núñez-García , Dayanira S. Arellano-Suárez , Claudia Wong-Arámbula , Irma López-Martínez , Rosa M. Wong-Chew , Guadalupe Ayora-Talavera
The most widely used class of antivirals available for Influenza treatment are the neuraminidase inhibitors (NAI) Oseltamivir and Zanamivir. However, amino acid (AA) substitutions in the neuraminidase may cause reduced inhibition or high antiviral resistance. In Mexico, the current state of knowledge about NAI susceptibility is scarce, in this study we report the results of 14 years of Influenza surveillance by phenotypic and genotypic methods. A total of 255 isolates were assessed with the NAI assay, including Influenza A(H1N1)pdm09, A(H3N2) and Influenza B (IBV). Furthermore, 827 sequences contained in the GISAID platform were analyzed in search of relevant mutations.Overall, five isolates showed highly reduced inhibition or reduced inhibition to Oseltamivir, and two showed reduced inhibition to Zanamivir in the NAI assays. Additionally, five A(H1N1)pdm09 sequences from the GISAID possessed AA substitutions associated to reduced inhibition to Oseltamivir and none to Zanamivir. Oseltamivir resistant A(H1N1)pdm09 harbored the H275Y mutation. No genetic mutations were identified in Influenza A(H3N2) and IBV. Overall, these results show that in Mexico the rate of NAI resistance is low (0.6%), but it is essential to continue the Influenza surveillance in order to understand the drug susceptibility of circulating strains.
目前用于治疗流感的最广泛的抗病毒药物是神经氨酸酶抑制剂(NAI)奥司他韦和扎那米韦。然而,神经氨酸酶中的氨基酸(AA)置换可能会导致抑制作用减弱或产生较高的抗病毒耐药性。在墨西哥,目前对 NAI 敏感性的了解还很少,在本研究中,我们报告了 14 年来通过表型和基因型方法进行流感监测的结果。共对 255 个分离株进行了 NAI 检测评估,其中包括甲型 H1N1、甲型 H3N2 和乙型流感 (IBV)。此外,还对 GISAID 平台中包含的 827 个序列进行了分析,以寻找相关突变。总体而言,在 NAI 试验中,有 5 个分离株对奥司他韦的抑制作用高度减弱或减弱,2 个分离株对扎那米韦的抑制作用减弱。此外,GISAID 中的 5 个 A(H1N1)pdm09 序列具有 AA 取代,对奥司他韦的抑制作用降低,对扎那米韦的抑制作用则没有降低。对奥司他韦耐药的 A(H1N1)pdm09 存在 H275Y 突变。甲型 H3N2 流感和 IBV 没有发现基因突变。总之,这些结果表明,墨西哥的非那西丁抗药率较低(0.6%),但必须继续进行流感监测,以了解流行毒株的药物敏感性。
{"title":"Low antiviral resistance in Influenza A and B viruses isolated in Mexico from 2010 to 2023","authors":"Diana A. Franco-May , Jesús Gómez-Carballo , Gisela Barrera-Badillo , María N. Cruz-Ortíz , Tatiana E. Núñez-García , Dayanira S. Arellano-Suárez , Claudia Wong-Arámbula , Irma López-Martínez , Rosa M. Wong-Chew , Guadalupe Ayora-Talavera","doi":"10.1016/j.antiviral.2024.105918","DOIUrl":"10.1016/j.antiviral.2024.105918","url":null,"abstract":"<div><p>The most widely used class of antivirals available for Influenza treatment are the neuraminidase inhibitors (NAI) Oseltamivir and Zanamivir. However, amino acid (AA) substitutions in the neuraminidase may cause reduced inhibition or high antiviral resistance. In Mexico, the current state of knowledge about NAI susceptibility is scarce, in this study we report the results of 14 years of Influenza surveillance by phenotypic and genotypic methods. A total of 255 isolates were assessed with the NAI assay, including Influenza A(H1N1)pdm09, A(H3N2) and Influenza B (IBV). Furthermore, 827 sequences contained in the GISAID platform were analyzed in search of relevant mutations.Overall, five isolates showed highly reduced inhibition or reduced inhibition to Oseltamivir, and two showed reduced inhibition to Zanamivir in the NAI assays. Additionally, five A(H1N1)pdm09 sequences from the GISAID possessed AA substitutions associated to reduced inhibition to Oseltamivir and none to Zanamivir. Oseltamivir resistant A(H1N1)pdm09 harbored the H275Y mutation. No genetic mutations were identified in Influenza A(H3N2) and IBV. Overall, these results show that in Mexico the rate of NAI resistance is low (0.6%), but it is essential to continue the Influenza surveillance in order to understand the drug susceptibility of circulating strains.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":null,"pages":null},"PeriodicalIF":7.6,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S016635422400127X/pdfft?md5=00d6985cb1161a85d5476f6d32a0254b&pid=1-s2.0-S016635422400127X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141143034","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}
Pub Date : 2024-05-21DOI: 10.1016/j.antiviral.2024.105917
Yucai Liang , Weiling Xiao , Yuan Peng , Shengshuo Zhang , Jinhua Dong , Jun Zhao , Yuhui Wang , Mengtao Zhang , Zhijun Liu , Bowen Yu
The Fc-fused receptor binding domain (RBD-Fc) vaccine for SARS-CoV-2 has garnered significant attention for its capacity to provide effective and specific immune protection. However, its immunogenicity is limited, highlighting the need for improvement in clinical application. Nanoparticle delivery has been shown to be an effective method for enhancing antigen immunogenicity. In this study, we developed bivalent nanoparticle recombinant protein vaccines by assembling the RBD-Fc of SARS-CoV-2 and Fc-binding homo-oligomers o42.1 and i52.3 into octahedral and icosahedral nanoparticles. The formation of RBD-Fc nanoparticles was confirmed through structural characterization and cell binding experiments. Compared to RBD-Fc dimers, the nanoparticle vaccines induced more potent neutralizing antibodies (nAb) and stronger cellular immune responses. Therefore, using bivalent nanoparticle vaccines based on RBD-Fc presents a promising vaccination strategy against SARS-CoV-2 and offers a universal approach for enhancing the immunogenicity of Fc fusion protein vaccines.
针对 SARS-CoV-2 的 Fc 融合受体结合域(RBD-Fc)疫苗因其提供有效和特异性免疫保护的能力而备受关注。然而,其免疫原性有限,在临床应用中亟待改进。纳米颗粒递送已被证明是提高抗原免疫原性的有效方法。在这项研究中,我们将 SARS-CoV-2 的 RBD-Fc 和 Fc 结合同源异构体 o42.1 和 i52.3 组装成八面体和二十面体纳米颗粒,开发了双价纳米颗粒重组蛋白疫苗。RBD-Fc 纳米粒子的形成通过结构表征和细胞结合实验得到了证实。与 RBD-Fc 二聚体相比,纳米颗粒疫苗能诱导更强的中和抗体(nAb)和更强的细胞免疫反应。因此,使用基于 RBD-Fc 的二价纳米颗粒疫苗是一种很有前景的 SARS-CoV-2 疫苗接种策略,并为增强 Fc 融合蛋白疫苗的免疫原性提供了一种通用方法。
{"title":"Development of nanoparticle vaccines utilizing designed Fc-binding homo-oligomers and RBD-Fc of SARS-CoV-2","authors":"Yucai Liang , Weiling Xiao , Yuan Peng , Shengshuo Zhang , Jinhua Dong , Jun Zhao , Yuhui Wang , Mengtao Zhang , Zhijun Liu , Bowen Yu","doi":"10.1016/j.antiviral.2024.105917","DOIUrl":"10.1016/j.antiviral.2024.105917","url":null,"abstract":"<div><p>The Fc-fused receptor binding domain (RBD-Fc) vaccine for SARS-CoV-2 has garnered significant attention for its capacity to provide effective and specific immune protection. However, its immunogenicity is limited, highlighting the need for improvement in clinical application. Nanoparticle delivery has been shown to be an effective method for enhancing antigen immunogenicity. In this study, we developed bivalent nanoparticle recombinant protein vaccines by assembling the RBD-Fc of SARS-CoV-2 and Fc-binding homo-oligomers o42.1 and i52.3 into octahedral and icosahedral nanoparticles. The formation of RBD-Fc nanoparticles was confirmed through structural characterization and cell binding experiments. Compared to RBD-Fc dimers, the nanoparticle vaccines induced more potent neutralizing antibodies (nAb) and stronger cellular immune responses. Therefore, using bivalent nanoparticle vaccines based on RBD-Fc presents a promising vaccination strategy against SARS-CoV-2 and offers a universal approach for enhancing the immunogenicity of Fc fusion protein vaccines.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":null,"pages":null},"PeriodicalIF":7.6,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086059","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}
Pub Date : 2024-05-21DOI: 10.1016/j.antiviral.2024.105916
Na Jiang , Yating He , Jing Wu , Qiao You , Rui Zhang , Min Cheng , Bingxin Liu , Yurong Cai , Ruining Lyu , Zhiwei Wu
The severe fever with thrombocytopenia syndrome virus (SFTSV) is a novel phlebovirus, recently being officially renamed as Dabie bandavirus, and a causative agent for an emerging infectious disease associated with high fatality. Effective therapeutics and vaccines are lacking and disease pathogenesis is yet to be fully elucidated. In our effort to identify new SFTSV inhibitory molecules, 6-Thioguanine (6-TG) was found to potently inhibit SFTSV infection. 6-TG has been widely used as therapeutic agent since the approval of the Food and Drug Administration in the 1960s. In the current study, we showed that 6-TG was a potent inhibitor of SFTSV infection with 50% effective concentrations (EC50) of 3.465 μM in VeroE6 cells, and 1.848 μM in HUVEC cells. The selectivity index (SI) was >57 in VeroE6 cells and >108 in HUVEC cells, respectively. The SFTSV RNA transcription, protein synthesis, and progeny virions were reduced in a dose dependent manner by the presence of 6-TG in the in vitro infection assay. Further study on the mechanism of the anti-SFTSV activity showed that 6-TG downregulated the production of early growth response gene-1 (EGR1). Using gene silencing and overexpression, we further confirmed that EGR1 was a host restriction factor against SFTSV. Meanwhile, treatment of infected experimental animals with 6-TG inhibited SFTSV infection and alleviated multi-organ dysfunction. In conclusion, we have identified 6-TG as an effective inhibitor of SFTSV replication via the inhibition of EGR1 expression. Further studies are needed to evaluate of 6-TG as a potential therapeutic for treating SFTS.
{"title":"6-Thioguanine inhibits severe fever with thrombocytopenia syndrome virus through suppression of EGR1","authors":"Na Jiang , Yating He , Jing Wu , Qiao You , Rui Zhang , Min Cheng , Bingxin Liu , Yurong Cai , Ruining Lyu , Zhiwei Wu","doi":"10.1016/j.antiviral.2024.105916","DOIUrl":"10.1016/j.antiviral.2024.105916","url":null,"abstract":"<div><p>The severe fever with thrombocytopenia syndrome virus (SFTSV) is a novel <em>phlebovirus</em>, recently being officially renamed as Dabie bandavirus, and a causative agent for an emerging infectious disease associated with high fatality. Effective therapeutics and vaccines are lacking and disease pathogenesis is yet to be fully elucidated. In our effort to identify new SFTSV inhibitory molecules, 6-Thioguanine (6-TG) was found to potently inhibit SFTSV infection. 6-TG has been widely used as therapeutic agent since the approval of the Food and Drug Administration in the 1960s. In the current study, we showed that 6-TG was a potent inhibitor of SFTSV infection with 50% effective concentrations (EC<sub>50</sub>) of 3.465 μM in VeroE6 cells, and 1.848 μM in HUVEC cells. The selectivity index (SI) was >57 in VeroE6 cells and >108 in HUVEC cells, respectively. The SFTSV RNA transcription, protein synthesis, and progeny virions were reduced in a dose dependent manner by the presence of 6-TG in the <em>in vitro</em> infection assay. Further study on the mechanism of the anti-SFTSV activity showed that 6-TG downregulated the production of early growth response gene-1 (EGR1). Using gene silencing and overexpression, we further confirmed that EGR1 was a host restriction factor against SFTSV. Meanwhile, treatment of infected experimental animals with 6-TG inhibited SFTSV infection and alleviated multi-organ dysfunction. In conclusion, we have identified 6-TG as an effective inhibitor of SFTSV replication via the inhibition of EGR1 expression. Further studies are needed to evaluate of 6-TG as a potential therapeutic for treating SFTS.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":null,"pages":null},"PeriodicalIF":7.6,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141079943","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}
Pub Date : 2024-05-20DOI: 10.1016/j.antiviral.2024.105915
Bing Liang Alvin Chew , Qi Pan , Hongli Hu , Dahai Luo
The genus of flavivirus includes many mosquito-borne human pathogens, such as Zika (ZIKV) and the four serotypes of dengue (DENV1-4) viruses, that affect billions of people as evidenced by epidemics and endemicity in many countries and regions in the world. Among the 10 viral proteins encoded by the viral genome, the nonstructural protein 1 (NS1) is the only secreted protein and has been used as a diagnostic biomarker. NS1 has also been an attractive target for its biotherapeutic potential as a vaccine antigen. This review focuses on the recent advances in the structural landscape of the secreted NS1 (sNS1) and its complex with monoclonal antibodies (mAbs). NS1 forms an obligatory dimer, and upon secretion, it has been reported to be hexametric (trimeric dimers) that could dissociate and bind to the epithelial cell membrane. However, high-resolution structural information has been missing about the high-order oligomeric states of sNS1. Several cryoEM studies have since shown that DENV and ZIKV recombinant sNS1 (rsNS1) are in dynamic equilibrium of dimer-tetramer-hexamer states, with tetramer being the predominant form. It was recently revealed that infection-derived sNS1 (isNS1) forms a complex of the NS1 dimer partially embedded in a High-Density Lipoprotein (HDL) particle. Structures of NS1 in complexes with mAbs have also been reported which shed light on their protective roles during infection. The biological significance of the diversity of NS1 oligomeric states remains to be further studied, to inform future research on flaviviral pathogenesis and the development of therapeutics and vaccines. Given the polymorphism of flavivirus NS1 across sample types with variations in antigenicity, we propose a nomenclature to accurately define NS1 based on the localization and origin.
{"title":"Structural biology of flavivirus NS1 protein and its antibody complexes","authors":"Bing Liang Alvin Chew , Qi Pan , Hongli Hu , Dahai Luo","doi":"10.1016/j.antiviral.2024.105915","DOIUrl":"10.1016/j.antiviral.2024.105915","url":null,"abstract":"<div><p>The genus of flavivirus includes many mosquito-borne human pathogens, such as Zika (ZIKV) and the four serotypes of dengue (DENV1-4) viruses, that affect billions of people as evidenced by epidemics and endemicity in many countries and regions in the world. Among the 10 viral proteins encoded by the viral genome, the nonstructural protein 1 (NS1) is the only secreted protein and has been used as a diagnostic biomarker. NS1 has also been an attractive target for its biotherapeutic potential as a vaccine antigen. This review focuses on the recent advances in the structural landscape of the secreted NS1 (sNS1) and its complex with monoclonal antibodies (mAbs). NS1 forms an obligatory dimer, and upon secretion, it has been reported to be hexametric (trimeric dimers) that could dissociate and bind to the epithelial cell membrane. However, high-resolution structural information has been missing about the high-order oligomeric states of sNS1. Several cryoEM studies have since shown that DENV and ZIKV recombinant sNS1 (rsNS1) are in dynamic equilibrium of dimer-tetramer-hexamer states, with tetramer being the predominant form. It was recently revealed that infection-derived sNS1 (isNS1) forms a complex of the NS1 dimer partially embedded in a High-Density Lipoprotein (HDL) particle. Structures of NS1 in complexes with mAbs have also been reported which shed light on their protective roles during infection. The biological significance of the diversity of NS1 oligomeric states remains to be further studied, to inform future research on flaviviral pathogenesis and the development of therapeutics and vaccines. Given the polymorphism of flavivirus NS1 across sample types with variations in antigenicity, we propose a nomenclature to accurately define NS1 based on the localization and origin.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":null,"pages":null},"PeriodicalIF":7.6,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0166354224001244/pdfft?md5=5fb1baf095c37122806b74c688b6f5a7&pid=1-s2.0-S0166354224001244-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141079953","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}
Pub Date : 2024-05-19DOI: 10.1016/j.antiviral.2024.105907
Brecht Bonneux , Afzaal Shareef , Sergey Tcherniuk , Brandon Anson , Suzanne de Bruyn , Nick Verheyen , Kim Thys , Nádia Conceição-Neto , Marcia Van Ginderen , Leen Kwanten , Nina Ysebaert , Luc Vranckx , Elien Peeters , Ellen Lanckacker , Jack M. Gallup , Panchan Sitthicharoenchai , Sarhad Alnajjar , Mark R. Ackermann , Suraj Adhikary , Anusarka Bhaumik , Florence Herschke
Respiratory syncytial virus (RSV) can cause pulmonary complications in infants, elderly and immunocompromised patients. While two vaccines and two prophylactic monoclonal antibodies are now available, treatment options are still needed. JNJ-7184 is a non-nucleoside inhibitor of the RSV-Large (L) polymerase, displaying potent inhibition of both RSV-A and -B strains. Resistance selection and hydrogen-deuterium exchange experiments suggest JNJ-7184 binds RSV-L in the connector domain. JNJ-7184 prevents RSV replication and transcription by inhibiting initiation or early elongation. JNJ-7184 is effective in air-liquid interface cultures and therapeutically in neonatal lambs, acting to drastically reverse the appearance of lung pathology.
{"title":"JNJ-7184, a respiratory syncytial virus inhibitor targeting the connector domain of the viral polymerase","authors":"Brecht Bonneux , Afzaal Shareef , Sergey Tcherniuk , Brandon Anson , Suzanne de Bruyn , Nick Verheyen , Kim Thys , Nádia Conceição-Neto , Marcia Van Ginderen , Leen Kwanten , Nina Ysebaert , Luc Vranckx , Elien Peeters , Ellen Lanckacker , Jack M. Gallup , Panchan Sitthicharoenchai , Sarhad Alnajjar , Mark R. Ackermann , Suraj Adhikary , Anusarka Bhaumik , Florence Herschke","doi":"10.1016/j.antiviral.2024.105907","DOIUrl":"10.1016/j.antiviral.2024.105907","url":null,"abstract":"<div><p>Respiratory syncytial virus (RSV) can cause pulmonary complications in infants, elderly and immunocompromised patients. While two vaccines and two prophylactic monoclonal antibodies are now available, treatment options are still needed. JNJ-7184 is a non-nucleoside inhibitor of the RSV-Large (L) polymerase, displaying potent inhibition of both RSV-A and -B strains. Resistance selection and hydrogen-deuterium exchange experiments suggest JNJ-7184 binds RSV-L in the connector domain. JNJ-7184 prevents RSV replication and transcription by inhibiting initiation or early elongation. JNJ-7184 is effective in air-liquid interface cultures and therapeutically in neonatal lambs, acting to drastically reverse the appearance of lung pathology.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":null,"pages":null},"PeriodicalIF":7.6,"publicationDate":"2024-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141075095","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}
Pub Date : 2024-05-15DOI: 10.1016/j.antiviral.2024.105914
Francisco J. Mancebo , Marcos Nuévalos , Jaanam Lalchandani , Antonio J. Martín Galiano , Mario Fernández-Ruiz , José María Aguado , Estéfani García-Ríos , Pilar Pérez-Romero
Due to the severity of CMV infection in immunocompromised individuals the development of a vaccine has been declared a priority. However, despite the efforts made there is no yet a vaccine available for clinical use. We designed an approach to identify new CMV antigens able to inducing a broad immune response that could be used in future vaccine formulations.
We have used serum samples from 28 kidney transplant recipients, with a previously acquired CMV-specific immune response to identify viral proteins that were recognized by the antibodies present in the patient serum samples by Western blot. A band of approximately 45 kDa, identified as UL44, was detected by most serum samples. UL44 immunogenicity was tested in BALB/c mice that received three doses of the UL44-pcDNA DNA vaccine. UL44 elicited both, a strong antibody response and CMV-specific cellular response. Using bioinformatic analysis we demonstrated that UL44 is a highly conserved protein and contains epitopes that are able to activate CD8 lymphocytes of the most common HLA alleles in the world population. We constructed a UL44 ORF deletion mutant virus that produced no viral progeny, suggesting that UL44 is an essential viral protein. In addition, other authors have demonstrated that UL44 is one of the most abundant viral proteins after infection and have suggested an essential role of UL44 in viral replication. Altogether, our data suggests that UL44 is a potent antigen, and favored by its abundance, it may be a good candidate to include in a vaccine formulation.
{"title":"Cytomegalovirus UL44 protein induces a potent T-cell immune response in mice","authors":"Francisco J. Mancebo , Marcos Nuévalos , Jaanam Lalchandani , Antonio J. Martín Galiano , Mario Fernández-Ruiz , José María Aguado , Estéfani García-Ríos , Pilar Pérez-Romero","doi":"10.1016/j.antiviral.2024.105914","DOIUrl":"10.1016/j.antiviral.2024.105914","url":null,"abstract":"<div><p>Due to the severity of CMV infection in immunocompromised individuals the development of a vaccine has been declared a priority. However, despite the efforts made there is no yet a vaccine available for clinical use. We designed an approach to identify new CMV antigens able to inducing a broad immune response that could be used in future vaccine formulations.</p><p>We have used serum samples from 28 kidney transplant recipients, with a previously acquired CMV-specific immune response to identify viral proteins that were recognized by the antibodies present in the patient serum samples by Western blot. A band of approximately 45 kDa, identified as UL44, was detected by most serum samples. UL44 immunogenicity was tested in BALB/c mice that received three doses of the UL44-pcDNA DNA vaccine. UL44 elicited both, a strong antibody response and CMV-specific cellular response. Using bioinformatic analysis we demonstrated that UL44 is a highly conserved protein and contains epitopes that are able to activate CD8 lymphocytes of the most common HLA alleles in the world population. We constructed a UL44 ORF deletion mutant virus that produced no viral progeny, suggesting that UL44 is an essential viral protein. In addition, other authors have demonstrated that UL44 is one of the most abundant viral proteins after infection and have suggested an essential role of UL44 in viral replication. Altogether, our data suggests that UL44 is a potent antigen, and favored by its abundance, it may be a good candidate to include in a vaccine formulation.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":null,"pages":null},"PeriodicalIF":7.6,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140956046","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}