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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
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。
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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
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。
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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
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 Epub Date: 2024-10-28 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
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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
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。
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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
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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引用次数: 0
Vemurafenib inhibits the replication of diabetogenic enteroviruses in intestinal epithelial and pancreatic beta cells 维莫非尼抑制致糖尿病肠道病毒在肠上皮细胞和胰腺β细胞中的复制。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-15 DOI: 10.1016/j.antiviral.2024.106021
Enteroviruses, which infect via the gut, have been implicated in type 1 diabetes (T1D) development. Prolonged faecal shedding of enterovirus has been associated with islet autoimmunity. Additionally, enteroviral proteins and viral RNA have been detected in the pancreatic islets of individuals with recent-onset T1D, implicating their possible role in beta cell destruction. Despite this, no approved antiviral drugs currently exist that specifically target enterovirus infections for utilisation in disease interventions.
Drug repurposing allows for the discovery of new clinical uses for existing drugs and can expedite drug discovery. Previously, the cancer drug Vemurafenib demonstrated unprecedented antiviral activity against several enteroviruses. In the present study, we assessed the efficacy of Vemurafenib and an analogue thereof in preventing infection or reducing the replication of enteroviruses associated with T1D. We tested Vemurafenib in intestinal epithelial cells (IECs) and insulin-producing beta cells. Additionally, we established a protocol for infecting human stem cell-derived islets (SC-islets) and used Vemurafenib and its analogue in this model.
Our studies revealed that Vemurafenib exhibited strong antiviral properties in IECs and a beta cell line. The antiviral effect was also seen with the Vemurafenib analogue. SC-islets expressed the viral receptors CAR and DAF, with their highest expression in insulin- and glucagon-positive cells, respectively. SC-islets were successfully infected by CVBs and the antiviral activity of Vemurafenib and its analogue was confirmed in most SC-islet batches.
In summary, our observations suggest that Vemurafenib and its analogue warrant further exploration as potential antiviral agents for the treatment of enterovirus-induced diseases, including T1D.
通过肠道感染的肠道病毒与 1 型糖尿病(T1D)的发病有关。肠道病毒的长期粪便脱落与胰岛自身免疫有关。此外,在新近发病的 T1D 患者的胰岛中也检测到了肠道病毒蛋白和病毒 RNA,这表明它们可能在β细胞破坏中发挥作用。尽管如此,目前还没有获得批准的专门针对肠道病毒感染的抗病毒药物可用于疾病干预。药物再利用允许为现有药物发现新的临床用途,并能加快药物发现。此前,抗癌药物 Vemurafenib 对几种肠道病毒表现出了前所未有的抗病毒活性。在本研究中,我们评估了 Vemurafenib 及其类似物在预防感染或减少与 T1D 相关的肠道病毒复制方面的功效。我们在肠上皮细胞(IECs)和胰岛素分泌β细胞中测试了维莫非尼。此外,我们还制定了感染人类干细胞衍生胰岛(SC-islets)的方案,并在该模型中使用了Vemurafenib及其类似物。我们的研究显示,Vemurafenib 在 IECs 和 beta 细胞系中表现出很强的抗病毒特性。Vemurafenib类似物也具有抗病毒作用。SC小体表达病毒受体CAR和DAF,它们分别在胰岛素阳性细胞和胰高血糖素阳性细胞中的表达量最高。SC-islet 成功感染了 CVB,而且大多数批次的 SC-islet 都证实了 Vemurafenib 及其类似物的抗病毒活性。总之,我们的观察结果表明,Vemurafenib 及其类似物作为治疗肠道病毒引起的疾病(包括 T1D)的潜在抗病毒药物值得进一步探索。
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引用次数: 0
Bictegravir alters glucose tolerance in vivo and causes hepatic mitochondrial dysfunction 比特拉韦会改变体内葡萄糖耐量并导致肝线粒体功能障碍。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-15 DOI: 10.1016/j.antiviral.2024.106020
Growing evidence associates antiretroviral therapies containing integrase strand transfer inhibitors or tenofovir alafenamide (TAF) with increased weight gain and metabolic diseases, but the underlying mechanisms remain unclear. This study evaluated the impact of lamivudine, dolutegravir (DTG), bictegravir (BIC), tenofovir disoproxil fumarate, and TAF on metabolic alterations, and explored glucose homeostasis and mitochondrial stress as potential mechanisms. These pathways were analyzed both in vivo (C57BL/6J mice treated with the abovementioned drugs or vehicle for 16 weeks) and in vitro (in Hep3B cells). Mice treated with BIC exhibited higher glucose levels and a slower decrease during a glucose tolerance test. Functional enrichment analyses of livers from antiretroviral-treated mice revealed that only BIC altered the cellular response to insulin and induced a gluconeogenic-favoring profile, with Fgf21 playing a significant role. In vitro, BIC significantly reduced hepatocyte glucose uptake in a concentration-dependent manner, both under basal conditions and post-insulin stimulation, while the other drugs produced no significant changes. Hep3B cells treated with clinically relevant concentrations of BIC exhibited significant alterations in the mRNA expression of enzymes related to glucose metabolism. Both DTG and BIC reduced mitochondrial dehydrogenase activity, but only BIC increased reactive oxygen species, mitochondrial membrane potential, and cellular granularity, thereby indicating mitochondrial stress. BIC promoted mitochondrial dysfunction, modified carbohydrate metabolism and glucose consumption in hepatocytes, and altered glucose tolerance and gluconeogenesis regulation in mice. These findings suggest that BIC contributes to insulin resistance and diabetes in people living with HIV, warranting clinical studies to clarify its association with carbohydrate metabolism disorders.
越来越多的证据表明,含有整合酶链转移抑制剂或替诺福韦-阿拉非那胺(TAF)的抗逆转录病毒疗法与体重增加和代谢性疾病有关,但其潜在机制仍不清楚。本研究评估了拉米夫定、多替拉韦(DTG)、比特拉韦(BIC)、富马酸替诺福韦二吡呋酯和 TAF 对代谢改变的影响,并探讨了作为潜在机制的葡萄糖稳态和线粒体应激。对这些途径进行了体内(C57BL/6J小鼠,用上述药物或载体治疗16周)和体外(Hep3B细胞)分析。在葡萄糖耐量试验中,接受 BIC 治疗的小鼠表现出更高的葡萄糖水平和更慢的葡萄糖下降速度。对抗逆转录病毒治疗小鼠肝脏的功能富集分析表明,只有 BIC 改变了细胞对胰岛素的反应,并诱导了有利于葡萄糖生成的特征,其中 Fgf21 起了重要作用。在体外,无论是在基础条件下还是在胰岛素刺激后,BIC 都能以浓度依赖的方式显著降低肝细胞的葡萄糖摄取,而其他药物则不会产生显著变化。用临床相关浓度的 BIC 处理 Hep3B 细胞后,与葡萄糖代谢有关的酶的 mRNA 表达发生了明显变化。DTG 和 BIC 都降低了线粒体脱氢酶的活性,但只有 BIC 增加了活性氧、线粒体膜电位和细胞颗粒度,从而显示线粒体应激。BIC 促进了线粒体功能障碍,改变了肝细胞的碳水化合物代谢和葡萄糖消耗,并改变了小鼠的糖耐量和糖生成调节。这些研究结果表明,BIC 会导致艾滋病毒感染者的胰岛素抵抗和糖尿病,因此有必要进行临床研究,以明确其与碳水化合物代谢紊乱的关系。
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引用次数: 0
Circulating capsid-antibody-complexes (CACs) drive intrahepatic complement deposition and inform subclinical liver inflammation in chronic hepatitis B 循环中的囊膜抗体复合物(CAC)驱动肝内补体沉积,为慢性乙型肝炎的亚临床肝脏炎症提供信息
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-11 DOI: 10.1016/j.antiviral.2024.106017
Chronic infection with Hepatitis B Virus (HBV) often results in a dysfunctional virus-specific T cell response hampering viral clearance. Paradoxically, intrahepatic inflammatory responses that contribute more to liver histopathology than to viral suppression are commonly observed, which are widely believed to be cell mediated. The involvement of humoral immunity in this process however is not well documented. To investigate the possible roles of HBV Capsid-Antibody Complexes (CACs) in eliciting chronic liver inflammation, we developed a novel microplate-based assay for the quantification of CACs in serum. The CACs assay showed high sensitivity and specificity with its readout closely correlating with the molecular features of CACs. A cross-sectional study on untreated chronic hepatitis B (CHB) patients showed a 77% positive rate for CACs with significant association with alanine transaminase (ALT), intrahepatic inflammation, and complement deposition, suggestive of its functional role in hepatic injury. Multiple staining of complement activation fragment C4d with major leukocyte and myofibroblast markers revealed an intertwined picture in periportal area with a morphology reminiscent of “piecemeal necrosis”. In a pooled cohort with ALT levels lower than 40 IU/ml, CACs alone revealed subclinical liver inflammation. We provide definitive evidence for a causative role for CACs in complement-mediated intrahepatic immunopathology, an additional mechanism contributing to liver damage in CHB. Assessment of CACs in serum complements current clinical markers for assessing CHB associated inflammation.
慢性乙型肝炎病毒(HBV)感染通常会导致病毒特异性 T 细胞反应失调,阻碍病毒清除。矛盾的是,肝内炎症反应对肝脏组织病理学的影响比对病毒抑制的影响更大,人们普遍认为这种反应是由细胞介导的。然而,体液免疫在这一过程中的参与并没有很好的记录。为了研究 HBV 荚膜-抗体复合物(CACs)在诱发慢性肝脏炎症中可能发挥的作用,我们开发了一种基于微孔板的新型检测方法,用于定量检测血清中的 CACs。CACs 检测法显示出很高的灵敏度和特异性,其读数与 CACs 的分子特征密切相关。一项针对未经治疗的慢性乙型肝炎(CHB)患者的横断面研究显示,CACs 的阳性率为 77%,且与丙氨酸转氨酶(ALT)、肝内炎症和补体沉积密切相关,表明其在肝损伤中的功能性作用。补体活化片段 C4d 与主要白细胞和肌成纤维细胞标记物的多重染色显示,肝周围区域的病变交织在一起,其形态令人联想到 "片状坏死"。在 ALT 水平低于 40 IU/ml 的汇集队列中,仅 CACs 就显示了亚临床肝脏炎症。我们为 CACs 在补体介导的肝内免疫病理中的致病作用提供了确凿证据,而补体介导的肝内免疫病理是导致 CHB 肝损伤的又一机制。对血清中 CACs 的评估补充了目前评估 CHB 相关炎症的临床标记物。
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引用次数: 0
Design and biological evaluation of candidate drugs against zoonotic porcine deltacoronavirus (PDCoV) 针对人畜共患猪三角花叶病毒(PDCoV)的候选药物的设计和生物学评价
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-10 DOI: 10.1016/j.antiviral.2024.106019
Porcine deltacoronavirus (PDCoV) is an emerging swine enteric coronavirus with zoonotic potential. PDCoV spillovers were recently detected in Haitian children with acute undifferentiated febrile illness, underscoring the urgent need to develop anti-PDCoV therapeutics. Coronavirus 3C-like protease (CoV 3CLpro) is essential for viral replication, and therefore provides an attractive target for drugs directed against CoV. Here, we initially evaluated the anti-PDCoV effect of Nirmatrelvir (PF-07321332), an FDA-approved anti-SARS-CoV-2 drug targeting viral 3CLpro. Regrettably, a very limited anti-PDCoV effect was achieved. By analyzing the binding modes of Nirmatrelvir with PDCoV 3CLpro and SARS-CoV-2 3CLpro, we demonstrated that the S2 pocket of 3CLpro is the primary factor underlying the differential inhibitory potency of Nirmatrelvir against different CoV 3CLpros. Based on the specific characteristics of the S2 pocket of PDCoV 3CLpro, four derivatives of Nirmatrelvir (compounds T1–T4) with substituted P2 moieties were synthesized. Compound T1, with an isobutyl at the P2 site, displayed improved anti-PDCoV activity in vitro (cell infection model) and in vivo (embryonated chicken egg infection model), and therefore is a potential candidate drug to combat PDCoV. Together, our results identify the substrate-binding mode and substrate specificity of PDCoV 3CLpro, providing insight into the optimization of Nirmatrelvir as an antiviral therapeutic agent against PDCoV.
猪三角冠状病毒(PDCoV)是一种新出现的猪肠道冠状病毒,具有人畜共患病的潜能。最近在海地急性未分化发热性疾病患儿中发现了 PDCoV 外溢,这突出表明迫切需要开发抗 PDCoV 治疗药物。冠状病毒 3C 样蛋白酶(CoV 3CLpro)对病毒复制至关重要,因此为针对 CoV 的药物提供了一个有吸引力的靶点。在这里,我们初步评估了Nirmatrelvir(PF-07321332)的抗PDCoV效果,Nirmatrelvir是FDA批准的一种以病毒3CLpro为靶点的抗SARS-CoV-2药物。遗憾的是,该药物的抗 PDCoV 效果非常有限。通过分析 Nirmatrelvir 与 PDCoV 3CLpro 和 SARS-CoV-2 3CLpro 的结合模式,我们证明 3CLpro 的 S2 口袋是 Nirmatrelvir 对不同 CoV 3CLpro 产生不同抑制效力的主要因素。根据 PDCoV 3CLpro S2 口袋的具体特征,我们合成了四种具有取代 P2 分子的 Nirmatrelvir 衍生物(化合物 T1-T4)。化合物 T1 的 P2 位点上有一个异丁基,在体外(细胞感染模型)和体内(胚胎鸡卵感染模型)显示出更好的抗 PDCoV 活性,因此是抗 PDCoV 的潜在候选药物。综上所述,我们的研究结果确定了 PDCoV 3CLpro 的底物结合模式和底物特异性,为优化 Nirmatrelvir 作为 PDCoV 抗病毒治疗药物提供了启示。
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