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Identification of a macrocyclic compound targeting the lassa virus polymerase 鉴定针对拉沙病毒聚合酶的大环化合物
IF 7.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-04 DOI: 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.

目前还没有针对拉沙病毒(LASV)感染的获批疫苗或疗法。为了找出具有抗拉沙病毒活性的化合物,我们在生物安全等级 4 级的条件下开展了一项基于细胞的筛选活动,并测试了近 60,000 种化合物对传染性报告基因拉沙病毒的活性。筛选出的新化合物包括几种结构相关的大环化合物。其中最有效的是 Mac128,它对报告病毒的半数致死浓度(EC50)为亚微摩尔,可抑制野生型 IV 族 LASV,并将病毒滴度降低 4 个数量级。机理研究表明,Mac128 可在聚合酶水平上抑制病毒复制。
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引用次数: 0
Performance of sofosbuvir and NITD008 in extrahepatic neuronal cells against HEV 索非布韦和 NITD008 在肝外神经元细胞中抗击 HEV 的效果。
IF 7.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-31 DOI: 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。
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引用次数: 0
The coronavirus nsp15 endoribonuclease: A puzzling protein and pertinent antiviral drug target 冠状病毒 nsp15 内切核酸酶:令人费解的蛋白质和相关的抗病毒药物靶点。
IF 7.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-31 DOI: 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.

SARS-CoV-2大流行促进了前所未有的研究工作,以更好地了解冠状病毒(CoV)感染的发病机制并开发有效的治疗方法。我们在此重点研究非结构蛋白 nsp15,它是病毒复制-转录复合体(RTC)的一个六聚体成分。Nsp15 具有尿苷特异性内切核酸酶(EndoU)活性,最近在病毒 RNA 中发现了一些特定的裂解位点。通过阻止病毒 dsRNA 的积累,EndoU 可以帮助病毒躲避先天性免疫反应的 RNA 传感器。nsp15 的免疫排斥特性已在多个 CoV 动物模型中牢固确立,并使其成为抗病毒治疗的相关靶点。寻找 nsp15 抑制剂的工作通常是通过化合物筛选进行的,而对 nsp15 蛋白结构的深入研究也在迅速发展。在本综述中,我们将从 nsp15 的结构、生化特性以及在 CoV 免疫逃避中的功能入手,广泛介绍这一迷人的蛋白质。接下来,我们将总结已报道的研究,在这些研究中,我们采用了化合物筛选或更合理的方法来确定合适的 nsp15 抑制剂开发线索。我们希望通过这种方式提高人们对这种独特的 CoV 蛋白的相关性和可药用性的认识。
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引用次数: 0
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 甘草酸与氨基酸甲酯的共轭物以主要蛋白酶为靶标,对野生型和耐尼马特韦的 SARS-CoV-2 变体具有抗病毒活性。
IF 7.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-29 DOI: 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.

COVID-19 大流行主要由 SARS-CoV-2 引起,其主要蛋白酶 Mpro 在病毒复制中起着关键作用,是抑制不同变体的潜在靶标。本研究从甘草酸(GL)衍生物与氨基酸甲基/乙基酯中发现了强效的 Mpro 抑制剂。在半合成的 17 种衍生物中,化合物 2、6、9 和 15 的碳水化合物分子中分别含有蛋氨酸甲酯、D-酪氨酸甲酯、谷氨酸甲酯和蛋氨酸,它们能显著抑制野生型 SARS-CoV-2 Mpro 介导的蛋白水解,IC50 值从 0.06 μM 到 0.84 μM 不等。它们在抑制突变 Mpro 变体(Mpro_P132H、Mpro_E166V、Mpro_P168A 和 Mpro_Q189I)的反式裂解方面也表现出了功效,IC50 值从 0.05 到 0.92 μM,超过了 nirmatrelvir(IC50:1.17∼152.9 μM)。分子建模显示,在 Mpro_E166V 与这些化合物的结构复合物中,缬氨酸 166 与 nirmatrelvir 的相互作用更强。此外,这些化合物还能有效抑制野生型 SARS-CoV-2 单轮感染颗粒(SRIPs)进入病毒后的过程,减轻病毒的细胞病理效应,减少复制驱动的 GFP 报告信号,以及野生型、Mpro_E166V 和 Mpro_Q189I SRIPs 的体外感染性,EC50 值从 0.02 μM 到 0.53 μM。然而,与野生型 SRIPs(EC50:0.06 μM)相比,nirmatrelvir 在抑制携带 Mpro_E166V 的突变 SARS-CoV-2 SRIPs(EC50:> 20 μM)和 Mpro_Q189I SRIPs(EC50:13.2 μM)的复制方面表现出明显的下降。总之,这项研究发现了四种 GL 衍生物,它们有望成为开发治疗各种 SARS-CoV-2 株系(包括 Omicron 和耐 nirmatrelvir 变异株)的先导化合物。
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引用次数: 0
Low antiviral resistance in Influenza A and B viruses isolated in Mexico from 2010 to 2023 2010 至 2023 年墨西哥分离的甲型和乙型流感病毒的低抗病毒性
IF 7.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-23 DOI: 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。
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引用次数: 0
Development of nanoparticle vaccines utilizing designed Fc-binding homo-oligomers and RBD-Fc of SARS-CoV-2 利用设计的 SARS-CoV-2 Fc 结合同源异构体和 RBD-Fc 开发纳米颗粒疫苗。
IF 7.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-21 DOI: 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。
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引用次数: 0
6-Thioguanine inhibits severe fever with thrombocytopenia syndrome virus through suppression of EGR1 6-硫鸟嘌呤通过抑制 EGR1 抑制严重发热伴血小板减少综合征病毒。
IF 7.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-21 DOI: 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.

严重发热伴血小板减少综合征病毒(SFTSV)是一种新型嗜血病毒,最近正式更名为达比带状疱疹病毒,是一种致死率很高的新发传染病的病原体。目前尚缺乏有效的治疗方法和疫苗,疾病的发病机制也尚未完全阐明。在我们寻找新的 SFTSV 抑制分子的过程中,我们发现 6-Thioguanine (6-TG) 能有效抑制 SFTSV 感染。自 20 世纪 60 年代获得美国食品药品管理局批准以来,6-硫鸟嘌呤已被广泛用作治疗药物。在本研究中,我们发现 6-TG 是一种强效的 SFTSV 感染抑制剂,在 VeroE6 细胞中的 50% 有效浓度(EC50)为 3.465 μM,在 HUVEC 细胞中为 1.848 μM。选择性指数(SI)在 VeroE6 细胞中> 57,在 HUVEC 细胞中> 108。在体外感染试验中,6-TG 的存在以剂量依赖的方式减少了 SFTSV RNA 转录、蛋白质合成和后代病毒。关于抗 SFTSV 活性机制的进一步研究表明,6-TG 下调了早期生长应答基因-1(EGR1)的产生。通过基因沉默和过表达,我们进一步证实了 EGR1 是一种抗 SFTSV 的宿主限制因子。同时,用 6-TG 治疗受感染的实验动物可抑制 SFTSV 感染并缓解多器官功能障碍。总之,我们发现 6-TG 可通过抑制 EGR1 的表达有效抑制 SFTSV 的复制。要评估 6-TG 作为治疗 SFTS 的潜在疗法还需要进一步的研究。
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引用次数: 0
Structural biology of flavivirus NS1 protein and its antibody complexes 黄热病病毒 NS1 蛋白及其抗体复合物的结构生物学。
IF 7.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-20 DOI: 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.

黄病毒属包括许多由蚊子传播的人类病原体,如寨卡(ZIKV)和登革热病毒的四个血清型(DENV1-4),它们影响着数十亿人,在世界许多国家和地区的流行和地方病流行就是证明。在病毒基因组编码的 10 种病毒蛋白中,非结构蛋白 1(NS1)是唯一的分泌蛋白,已被用作诊断生物标志物。NS1 作为疫苗抗原具有生物治疗潜力,因此也是一个极具吸引力的靶点。本综述将重点介绍分泌型 NS1(sNS1)结构及其与单克隆抗体(mAbs)复合物的最新进展。据报道,NS1 在分泌时会形成六聚体(三聚体二聚体),可以解离并与上皮细胞膜结合。然而,关于 sNS1 的高阶低聚物状态的高分辨率结构信息一直缺失。后来的几项冷冻电镜研究表明,DENV 和 ZIKV 重组 sNS1(rsNS1)处于二聚体-四聚体-六聚体的动态平衡状态,其中四聚体是最主要的形式。最近有研究发现,感染衍生的 sNS1(isNS1)形成了一个部分嵌入高密度脂蛋白(HDL)颗粒的 NS1 二聚体复合物。还有报道称,NS1 与 mAbs 复合物的结构揭示了它们在感染过程中的保护作用。NS1低聚物状态多样性的生物学意义仍有待进一步研究,以便为今后的黄病毒致病机理研究以及治疗药物和疫苗的开发提供信息。鉴于黄病毒 NS1 在不同样本类型中的多态性以及抗原性的变化,我们提出了一种命名法,以根据定位和来源准确定义 NS1。
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引用次数: 0
JNJ-7184, a respiratory syncytial virus inhibitor targeting the connector domain of the viral polymerase JNJ-7184 是一种针对病毒聚合酶接头结构域的呼吸道合胞病毒抑制剂。
IF 7.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-19 DOI: 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.

呼吸道合胞病毒(RSV)可导致婴儿、老年人和免疫力低下患者出现肺部并发症。虽然目前已有两种疫苗和两种预防性单克隆抗体,但仍需要治疗方案。JNJ-7184 是 RSV-Large (L) 聚合酶的非核苷抑制剂,对 RSV-A 和 -B 株都有很强的抑制作用。抗药性选择和氢氘交换实验表明,JNJ-7184 能在连接域结合 RSV-L。JNJ-7184 通过抑制起始或早期延伸来阻止 RSV 复制和转录。JNJ-7184 在气液界面培养和新生羔羊治疗中都很有效,能显著逆转肺部病变的出现。
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引用次数: 0
Cytomegalovirus UL44 protein induces a potent T-cell immune response in mice 巨细胞病毒 UL44 蛋白可诱导小鼠产生强烈的 T 细胞免疫反应。
IF 7.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-15 DOI: 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.

由于巨细胞病毒感染对免疫力低下者的严重影响,疫苗的开发已被列为当务之急。然而,尽管已经做出了很多努力,但目前还没有可用于临床的疫苗。我们设计了一种方法来识别能诱导广泛免疫反应的新 CMV 抗原,以用于未来的疫苗配方。我们使用了 28 位肾移植受者的血清样本,通过 Western 印迹法鉴定了患者血清样本中抗体可识别的病毒蛋白。大多数血清样本中都检测到了一条大约 45 kDa 的条带,被确定为 UL44。在接种了三剂 UL44-pcDNA DNA 疫苗的 BALB/c 小鼠中测试了 UL44 的免疫原性。UL44 可引起强烈的抗体反应和 CMV 特异性细胞反应。通过生物信息学分析,我们证明了 UL44 是一种高度保守的蛋白质,它包含的表位能够激活世界人口中最常见的 HLA 等位基因的 CD8 淋巴细胞。我们构建的 UL44 ORF 缺失突变病毒不产生病毒后代,这表明 UL44 是一种重要的病毒蛋白。此外,其他作者也证明 UL44 是感染后含量最高的病毒蛋白之一,并认为 UL44 在病毒复制中起着重要作用。总之,我们的数据表明,UL44 是一种强效抗原,由于其含量丰富,它可能是疫苗配方中的理想候选抗原。
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引用次数: 0
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Antiviral research
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