Antiviral research最新文献

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

IF 4.5 2区医学

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

{"title":"Replication capacity and susceptibility of nirmatrelvir-resistant mutants to next-generation Mpro inhibitors in a SARS-CoV-2 replicon system","authors":"","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":null,"pages":null},"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

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

IF 4.5 2区医学

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

{"title":"Berberine promotes K48-linked polyubiquitination of HNF4α, leading to the inhibition of HBV replication","authors":"","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":null,"pages":null},"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

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

Antiviral research Pub Date : 2024-11-01 DOI: 10.1016/j.antiviral.2024.106023

{"title":"Novel intercellular spread mode of respiratory syncytial virus contributes to neutralization escape","authors":"","doi":"10.1016/j.antiviral.2024.106023","DOIUrl":"10.1016/j.antiviral.2024.106023","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567043","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

Antiviral research Pub Date : 2024-10-29 DOI: 10.1016/j.antiviral.2024.106026

{"title":"Oral 3CL protease inhibitor ensitrelvir suppressed SARS-CoV-2 shedding and infection in a hamster aerosol transmission model","authors":"","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":null,"pages":null},"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

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

Antiviral research Pub 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

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

Antiviral research Pub Date : 2024-10-23 DOI: 10.1016/j.antiviral.2024.106024

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

Antiviral research Pub Date : 2024-10-15 DOI: 10.1016/j.antiviral.2024.106021

{"title":"Vemurafenib inhibits the replication of diabetogenic enteroviruses in intestinal epithelial and pancreatic beta cells","authors":"","doi":"10.1016/j.antiviral.2024.106021","DOIUrl":"10.1016/j.antiviral.2024.106021","url":null,"abstract":"<div><div>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.</div><div>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.</div><div>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.</div><div>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.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456785","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

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

Antiviral research Pub Date : 2024-10-15 DOI: 10.1016/j.antiviral.2024.106020

{"title":"Bictegravir alters glucose tolerance in vivo and causes hepatic mitochondrial dysfunction","authors":"","doi":"10.1016/j.antiviral.2024.106020","DOIUrl":"10.1016/j.antiviral.2024.106020","url":null,"abstract":"<div><div>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 <em>in vivo</em> (C57BL/6J mice treated with the abovementioned drugs or vehicle for 16 weeks) and <em>in vitro</em> (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 <em>Fgf21</em> playing a significant role. <em>In vitro</em>, 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.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456786","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

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

Antiviral research Pub Date : 2024-10-11 DOI: 10.1016/j.antiviral.2024.106017

{"title":"Circulating capsid-antibody-complexes (CACs) drive intrahepatic complement deposition and inform subclinical liver inflammation in chronic hepatitis B","authors":"","doi":"10.1016/j.antiviral.2024.106017","DOIUrl":"10.1016/j.antiviral.2024.106017","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142432764","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

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

Antiviral research Pub Date : 2024-10-10 DOI: 10.1016/j.antiviral.2024.106019

{"title":"Design and biological evaluation of candidate drugs against zoonotic porcine deltacoronavirus (PDCoV)","authors":"","doi":"10.1016/j.antiviral.2024.106019","DOIUrl":"10.1016/j.antiviral.2024.106019","url":null,"abstract":"<div><div>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 3CL<sup>pro</sup>) 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 3CL<sup>pro</sup>. Regrettably, a very limited anti-PDCoV effect was achieved. By analyzing the binding modes of Nirmatrelvir with PDCoV 3CL<sup>pro</sup> and SARS-CoV-2 3CL<sup>pro</sup>, we demonstrated that the S2 pocket of 3CL<sup>pro</sup> is the primary factor underlying the differential inhibitory potency of Nirmatrelvir against different CoV 3CL<sup>pro</sup>s. Based on the specific characteristics of the S2 pocket of PDCoV 3CL<sup>pro</sup>, 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 <em>in</em> <em>vitro</em> (cell infection model) and <em>in</em> <em>vivo</em> (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 3CL<sup>pro</sup>, providing insight into the optimization of Nirmatrelvir as an antiviral therapeutic agent against PDCoV.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142432763","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