Antiviral research最新文献_第5页

Intranasal vaccine induces broad and long-lasting immunity against the hemagglutinin stem of group 2 influenza A viruses 鼻内疫苗诱导对2组甲型流感病毒血凝素茎的广泛和持久免疫。

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-09-25 DOI: 10.1016/j.antiviral.2025.106284

Wanyue Zhang , Jérémie Prévost , Angela Sloan , Levi Tamming , Annabelle Pfeifle , Caroline Gravel , Sathya N. Thulasi Raman , Gary Van Domselaar , Michael J.W. Johnston , Lisheng Wang , Simon Sauve , Michael Rosu-Myles , Darwyn Kobasa , Anh Tran , Wangxue Chen , Xu Zhang , David Safronetz , Xuguang Li

Influenza A viruses are categorized into two phylogenetic groups (group 1 and group 2) based on the structure of their hemagglutinin (HA) protein. Within group 2, H3N2 poses a particular challenge due to its rapid evolution, limited vaccine efficacy, and association with more severe influenza seasons. Although T cell responses have been extensively studied in the context of vaccine-induced protection, HA stem (HA2)-specific T cell responses have been relatively understudied, especially those related to nasal immunity. To address this, we engineered an adenoviral vector vaccine (Ad-HA2) expressing a consensus hemagglutinin stem sequence, derived through bioinformatic analysis of all H3 strains. The vaccine conferred heterosubtypic protection against lethal challenges with either H3N2 or H7N9, both belonging to group 2 influenza A viruses, with protection lasting at least six months post-vaccination. Notably, the vaccine induced robust HA2-specific humoral and cell-mediated responses in the nasal-associated lymphoid tissue (NALT) of the upper respiratory tract, the first line of immune defense against inhaled pathogens. The vaccine also elicited significant levels of antibodies and T cell responses in the lower respiratory tract and pulmonary immune sites. Furthermore, circulating antibodies in the serum demonstrated effective antibody-dependent cellular cytotoxicity (ADCC) activity. Finally, using a peptide pool matrix screening approach combined with in silico verification, we identified an immunogenic C-terminus region of the HA2 consensus sequence that activated CD4⁺ and CD8⁺ T cells, which warrants further investigation. Collectively, these findings are informative for the design and evaluation of mucosal influenza vaccines targeting the hemagglutinin stem.

甲型流感病毒根据其血凝素（HA）蛋白的结构分为两个系统发育组（第1组和第2组）。在第2组中，H3N2由于其迅速演变、疫苗效力有限以及与更严重的流感季节有关而构成特别挑战。尽管在疫苗诱导保护的背景下，T细胞反应已被广泛研究，但对血凝素干细胞（HA2）特异性T细胞反应的研究相对不足，特别是与鼻腔免疫相关的T细胞反应。为了解决这个问题，我们设计了一种腺病毒载体疫苗（Ad-HA2），通过对所有H3菌株的生物信息学分析得出了一致的血凝素茎序列。该疫苗对H3N2或H7N9病毒（均属于2组A型流感病毒）的致命挑战具有异亚型保护作用，接种后保护作用至少持续6个月。值得注意的是，疫苗在上呼吸道的鼻相关淋巴组织（NALT）中诱导了强大的ha2特异性体液和细胞介导的反应，这是抵御吸入病原体的第一道免疫防线。该疫苗还在下呼吸道和肺部免疫部位引发了显著水平的抗体和T细胞反应。此外，血清中的循环抗体显示出有效的抗体依赖性细胞毒性（ADCC）活性。最后，使用肽池基质筛选方法结合计算机验证，我们确定了HA2共识序列的免疫原性c端区域，该区域可激活CD4+和CD8+ T细胞，值得进一步研究。总的来说，这些发现为设计和评估针对血凝素系统的粘膜流感疫苗提供了信息。

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引用次数: 0

CCHFV-M based DNA vaccine is highly immunogenic in multiple species and protects against challenge in cynomolgus macaques 基于CCHFV-M的DNA疫苗在多个物种中具有高度免疫原性，并保护食蟹猕猴免受攻击。

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-09-13 DOI: 10.1016/j.antiviral.2025.106282

John J. Suschak , Collin J. Fitzpatrick , Charles J. Shoemaker , Joshua D. Shamblin , Lauren E. White , Curtis R. Cline , Christina E. Douglas , Korey L. Delp , Trevor L.A. Burt , Kenise D. Lewis , Suma Ravulapalli , Susan Coyne , Carmen Ledesma-Feliciano , Gregg Wilson , Sarah L.W. Norris , Jennifer L. Scruggs , Ian Davis , Keersten M. Ricks , Christopher P. Stefan , Scott P. Olshner , Aura R. Garrison

Crimean-Congo hemorrhagic fever virus (CCHFV), a member of the Nairoviridae family, is the most widely distributed tick-borne virus of medical importance. There are no internationally licensed vaccines, and treatment is limited to supportive care. We previously developed a DNA vaccine expressing the full-length codon-optimized M-segment (CCHFV-M_Afg09), encoding the structural and non-structural viral glycoproteins that protects mice against CCHFV when delivered by intramuscular electroporation (IM-EP). Here, the immunogenicity and protective efficacy of the vaccine delivered by IM-EP was assessed in the non-lethal CCHFV cynomolgus macaque model. The vaccine elicited a significant antibody response to two glycoproteins, the structural G_C and non-structural GP38. CCHFV-M_Afg09 elicited quantifiable T-cell responses directed against the glycoproteins encoded within the M-segment, with anti-G_N immunity reaching significance. Upon intravenous infection with CCHFV, the vaccine protected 5/6 animals against viremia and reduced the pro-inflammatory response compared to sham vaccinated macaques. Numerous macaques also had detectable viral protein and viral RNA in several tissues 28 days post infection. In addition, we determined that an alternative delivery modality, jet injection, was immunogenic in both rabbits and mice, and conferred significant protection in mice. The simplicity and efficacy of disposable syringe needle-free injection system (NFIS) provides a pragmatic approach to advance the CCHF-M DNA vaccine into the clinic. Our M-segment based DNA vaccine elicits both cellular and humoral immunity and significant protection in mice and NHPs, demonstrating for the first time that a vaccine based on the glycoproteins alone is efficacious in the NHP model, which has not previously been shown.

克里米亚-刚果出血热病毒（CCHFV）是奈罗病毒科的一员，是分布最广泛的具有医学重要性的蜱传病毒。目前还没有获得国际许可的疫苗，治疗也仅限于支持性护理。我们之前开发了一种DNA疫苗，表达全长密码子优化的m片段（CCHFV- mafg09），编码结构和非结构病毒糖蛋白，通过肌内电穿孔（em - ep）递送时保护小鼠免受CCHFV的侵害。本研究在非致死性CCHFV食蟹猴模型中评估了IM-EP给药疫苗的免疫原性和保护效果。该疫苗引起了对两种糖蛋白（结构GC和非结构GP38）的显著抗体应答。CCHFV-MAfg09引发可量化的t细胞应答，直接针对m段编码的糖蛋白，具有抗gn免疫意义。在静脉感染CCHFV后，与未接种疫苗的猕猴相比，疫苗保护了5/6的动物免受病毒血症的侵害，并减少了促炎反应。许多猕猴在感染后28天的几个组织中也检测到病毒蛋白和病毒RNA。此外，我们确定了另一种给药方式，喷射注射，在兔子和小鼠中都具有免疫原性，并且在小鼠中具有显着的保护作用。一次性注射器无针注射系统（NFIS）的简单和有效为推进CCHF-M DNA疫苗进入临床提供了一种实用的方法。我们的基于m片段的DNA疫苗在小鼠和NHP中均可引起细胞和体液免疫，并具有显著的保护作用，首次证明仅基于糖蛋白的疫苗在NHP模型中有效，这在以前没有被证明过。

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引用次数: 0

Verteporfin is a broad-spectrum inhibitor of arboviruses and influences viral and host-based events 维替波芬是一种广谱虫媒病毒抑制剂，影响病毒和宿主事件。

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-09-12 DOI: 10.1016/j.antiviral.2025.106281

Carol A. Anderson , Stephanie V. Trefry , Michael D. Barrera , Niloufar Boghdeh , Sanskruthi Sreepangi , Lorreta Opoku , Maria F. Galarza , Amanda R. Bliss , Janard L. Bleach , Farhang Alem , Elsa Ronzier , Elaine S. Cerchin , Christina L. Gardner , Crystal W. Burke , Aarthi Narayanan

There is an unmet need for broadly effective therapeutic strategies to address the globally expanding health burden caused by vector-transmitted viruses. Protein-protein interactions involving host and viral proteins are key regulators of a productive viral infection and interruption of such interactions can exert broad-spectrum antiviral outcomes. Verteporfin (VP), a small molecule that is currently approved by the United States Food and Drug Administration (FDA) for the treatment of age-related macular degeneration and a known Yes-associated protein (YAP) inhibitor, was identified as a robust inhibitor of Venezuelan Equine Encephalitis Virus (VEEV) TC-83 strain from a protein-protein interaction inhibitor library. VP demonstrated a cell type independent reduction of viral load with inhibitory mechanism including reduction of nonstructural and structural protein levels. VP treatment also impacted its known target YAP, resulting in reduced expression of total and phosphorylated YAP in virus-infected cells. The in vivo assessment of VP in a lethal infection rodent model demonstrated early promise by increasing survival of infected animals, while also indicating the need for additional improvements in dosing strategy. Assessment of VP-mediated inhibition of other RNA viruses including Old- and New-world alphaviruses, a prototype flavivirus and bunyavirus demonstrated the potential of VP to function as a broad-spectrum inhibitor of vector-transmitted viruses.

对广泛有效的治疗战略的需求尚未得到满足，以应对媒介传播病毒造成的全球不断扩大的健康负担。涉及宿主和病毒蛋白的蛋白-蛋白相互作用是产生性病毒感染的关键调节因子，这种相互作用的中断可以发挥广谱抗病毒效果。维替波芬（VP）是一种小分子药物，目前已被美国食品和药物管理局（FDA）批准用于治疗老年性黄斑变性，也是一种已知的yes相关蛋白（YAP）抑制剂。从蛋白-蛋白相互作用抑制剂文库中，维替波芬被鉴定为委内瑞拉马脑炎病毒（VEEV） TC-83株的强效抑制剂。VP显示出一种不依赖于细胞类型的病毒载量的降低，其抑制机制包括非结构蛋白和结构蛋白水平的降低。VP处理也影响其已知靶点YAP，导致病毒感染细胞中总YAP和磷酸化YAP的表达降低。在致死性感染啮齿动物模型中对VP的体内评估显示，通过增加感染动物的存活率，VP有早期的希望，同时也表明需要进一步改进剂量策略。对VP介导的其他RNA病毒（包括旧世界和新世界α病毒、一种原型黄病毒和布尼亚病毒）的抑制作用的评估表明，VP具有作为媒介传播病毒的广谱抑制剂的潜力。

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引用次数: 0

Differential effects of antiretroviral HIV integrase inhibitors on vascular cell adhesion molecules 抗逆转录病毒HIV整合酶抑制剂对血管细胞粘附分子的差异影响。

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-09-11 DOI: 10.1016/j.antiviral.2025.106283

Ángeles Álvarez-Ribelles , Sandra Fernández-Rodríguez , Irene Carrasco-Hernández , Ana Blas-García , Víctor Collado-Díaz , Juan V. Esplugues

Integrase strand transfer inhibitors (INSTIs) have been linked to early cardiovascular (CV) complications. Despite the underlying mechanisms remain unclear, a proinflammatory effect has been suggested. Given the role of adhesion molecules in mediating endothelial interactions with leukocytes and platelets during vascular inflammation and thrombosis, we compared the impact of four INSTIs—dolutegravir (DTG), bictegravir (BIC), raltegravir (RAL), and cabotegravir (CAB)—and the non-nucleoside reverse transcriptase inhibitor doravirine (DOR), which is not associated with excessive CV risk, on adhesion molecule expression. Human blood, platelet-rich plasma, and endothelial cells from umbilical veins of healthy donors were incubated with clinically relevant drug concentrations and the expression of leukocyte, endothelium and platelet adhesion molecules was assessed by flow cytometry. BIC and CAB selectively activated neutrophils and monocytes, as evidenced by increased Mac-1 expression and L-selectin shedding. DTG, BIC, and DOR enhanced ICAM-1 expression on endothelial cells, while DTG and BIC also up-regulated VCAM-1, P-selectin and E-selectin levels. Additionally, DTG and BIC potentiated ADP-induced P-selectin expression in platelets. Overall, BIC produced the most significant pro-inflammatory changes, activating leukocytes, endothelial cells, and platelets; DTG primarily targeted the endothelium and platelets; CAB and DOR specifically activated leukocytes and endothelium, respectively, and RAL had no detectable effect. Our findings reveal distinct immunomodulatory profiles among the different INSTIs in vitro, rather than a class-wide effect. Future studies in patients with HIV will be needed to confirm the proinflammatory effects of DTG, BIC and CAB and to explore their potential implications for CV risk.

整合酶链转移抑制剂（INSTIs）与早期心血管（CV）并发症有关。尽管潜在的机制尚不清楚，但已经提出了一种促炎作用。考虑到粘附分子在血管炎症和血栓形成过程中介导内皮细胞和血小板相互作用的作用，我们比较了四种非核苷类逆转录酶抑制剂——多替格拉韦（DTG）、比替格拉韦（BIC）、雷替格拉韦（RAL）和卡替格拉韦（CAB）和非核苷类逆转录酶抑制剂多拉韦林（DOR）对粘附分子表达的影响，后者与心血管风险过高无关。用临床相关药物浓度培养人血、富血小板血浆和健康供者脐静脉内皮细胞，流式细胞术检测白细胞、内皮和血小板粘附分子的表达。BIC和CAB选择性地激活中性粒细胞和单核细胞，证明了增加的Mac-1表达和l -选择素的脱落。DTG、BIC和DOR增强内皮细胞ICAM-1表达，DTG和BIC上调VCAM-1、p-选择素和e -选择素水平。此外，DTG和BIC增强了adp诱导的p -选择素在血小板中的表达。总的来说，BIC产生了最显著的促炎改变，激活白细胞、内皮细胞和血小板；DTG主要作用于内皮细胞和血小板；CAB和DOR分别特异性激活白细胞和内皮细胞，而RAL无明显作用。我们的研究结果揭示了不同的免疫调节特征在体外不同的iniss，而不是类广泛的影响。未来在HIV患者中的研究将需要证实DTG、BIC和CAB的促炎作用，并探索它们对CV风险的潜在影响。

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引用次数: 0

Targeting of the cellular ATM rather than ATR kinase exhibits therapeutic potential during the lumpy skin disease virus infection in vivo and in vitro 在体内和体外，靶向细胞ATM而不是ATR激酶在肿块性皮肤病病毒感染期间显示出治疗潜力

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-09-06 DOI: 10.1016/j.antiviral.2025.106280

Shanhui Ren , Haotai Chen , Shasha Wang , Zaib Ur Rehman , Xiaolong Gao , Xue Yang , Xiangwei Wang , Xiangping Yin , Jianlin Han , Yuefeng Sun

Due to the lack of timely vaccine prevention and effective drug treatment, lumpy skin disease is increasingly becoming a global epidemic, including in China. There is an urgent need to explore the pathogenic mechanism of lumpy skin disease virus (LSDV) and develop practical therapeutic approaches. The present study provides concrete evidence for the simultaneous induction and activation of nuclear ATM-mediated double-strand break and ATR kinase-dependent single-strand break signaling cascades during LSDV replication in the cytoplasm. Specific drug-inhibitory experiments targeting ATM and ATR kinase activity have showed that LSDV activates the host deoxyribonucleic acid (DNA) damage response (DDR) to facilitate viral replication via ATM-Chk2 rather than the ATR-Chk1 signaling axis in vitro. Meanwhile, animal experiments corroborated the efficacy of an inhibitor drug targeting ATM kinase in decreasing the clinical symptoms of LSDV-infected cattle in vivo. These findings highlight how LSDV exploits the nuclear DDR pathway to enhance replication in the cytoplasmic viral factory, deepening our understanding of virus-host interactions and providing a new target for developing specific antiviral drugs and interventions.

由于缺乏及时的疫苗预防和有效的药物治疗，结节性皮肤病正日益成为一种全球流行病，包括在中国。目前迫切需要对肿块性皮肤病病毒（LSDV）的致病机制进行深入的研究，并找到切实可行的治疗方法。本研究为LSDV在细胞质复制过程中同时诱导和激活核atm介导的双链断裂和ATR激酶依赖的单链断裂信号级联提供了具体证据。针对ATM和ATR激酶活性的特异性药物抑制实验表明，LSDV在体外激活宿主脱氧核糖核酸（DNA）损伤反应（DDR），通过ATM- chk2而不是ATR- chk1信号轴促进病毒复制。同时，动物实验证实了一种以ATM激酶为靶点的抑制剂药物在体内能够减轻lsdv感染牛的临床症状。这些发现强调了LSDV如何利用核DDR途径增强细胞质病毒工厂中的复制，加深了我们对病毒-宿主相互作用的理解，并为开发特异性抗病毒药物和干预措施提供了新的靶点。

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引用次数: 0

Remarkable photodynamic activity of tetra-cationic porphyrins against Vaccinia virus and Monkeypox virus 四阳离子卟啉对牛痘病毒和猴痘病毒具有显著的光动力学活性

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-09-04 DOI: 10.1016/j.antiviral.2025.106279

Gilneia da Rosa , Paulo Henrique Hümmelgen Silva , José Valter Joaquim Silva Júnior , Micheli Mainardi Pillat , Bernardo Almeida Iglesias , Rudi Weiblen , Eduardo Furtado Flores

In this context, we evaluated the photodynamic effects of four cationic tetra-(pyridyl)porphyrins against Vaccinia virus Western Reserve (VACV WR) and Monkeypox virus (MPXV). The porphyrins were initially analyzed for cytotoxicity to Vero cells by MTT assay and the maximal non-cytotoxic concentrations were used in virucidal assays. For virucidal assays, VACV-WR (107.5 TCID50/mL) and MPXV suspensions (106.97 TCID50/mL) were incubated with porphyrins, exposed (or not) to white light conditions at 45 min. Aliquots of virus suspensions were collected and quantitated, comparing the titers with those of virus suspensions not exposed to porphyrins and/or to light. Porphyrins 4-PtTPyP, 3-H₂TMeP and 4-H₂TMeP exhibited light-dependent activity and completely inactivated VACV-WR and MPXV after 5, 30 and 45 min of light exposure, respectively. In contrast, derivative 3-PtTPyP inactivated the viruses even in the absence of white light exposure, a light-independent virucidal activity. Virucidal assays were performed in the presence/absence of ROS scavengers. Ascorbic acid (AA) was the only capable of completely inhibiting photodynamic inactivation by the three porphyrins. This indicates a type II photodynamic mechanism by singlet oxygen (¹O₂). These results demonstrated photodynamic inactivation of poxviruses by tetra-cationic porphyrins, supporting their potential use - especially 4-PtTPyP – for virus inactivation in many applications. These results also pave the way for testing porphyrin in PDT of poxvirus-induced cutaneous lesions. In addition, our data validated the use of VACV as a in vitro model for targeted MPXV virucidal testing.

在此背景下，我们评估了四种阳离子四（吡啶基）卟啉对牛痘病毒西部储备（VACV WR）和猴痘病毒（MPXV）的光动力学效应。用MTT法初步分析了卟啉对Vero细胞的细胞毒性，并将最大非细胞毒性浓度用于杀病毒试验。为了进行杀病毒实验，VACV-WR （107.5 TCID50/mL）和MPXV悬液（106.97 TCID50/mL）与卟啉一起孵育，在白光条件下暴露（或不暴露）45分钟。收集等量的病毒悬浮液并定量，与未暴露于卟啉和/或光的病毒悬浮液的滴度进行比较。卟啉4-PtTPyP、3-H2TMeP和4-H2TMeP分别在光照5、30和45 min后表现出光依赖性活性，并完全灭活VACV-WR和MPXV。相比之下，衍生物3-PtTPyP即使在没有白光照射的情况下也能灭活病毒，白光是一种不依赖于光的杀病毒活性。在存在或不存在活性氧清除剂的情况下进行杀病毒试验。抗坏血酸（AA）是唯一能完全抑制三种卟啉光动力失活的物质。这表明单线态氧（1O2）的II型光动力机制。这些结果证明了四阳离子卟啉对痘病毒的光动力失活，支持了它们的潜在用途，特别是4-PtTPyP在许多应用中对病毒的失活。这些结果也为在痘病毒诱发的皮肤病变的PDT中检测卟啉铺平了道路。此外，我们的数据验证了使用VACV作为靶向MPXV病毒检测的体外模型。

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引用次数: 0

Efficient eukaryotic expression and potent antiviral activity of a long-acting recombinant feline interferon-ω2-Fc fusion protein against major feline viruses 一种长效重组猫干扰素ω2- fc融合蛋白的高效真核表达及抗病毒活性研究。

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-09-03 DOI: 10.1016/j.antiviral.2025.106272

Yuwei Yang , Hetao Song , Ke Zhang , Siyin Wang , Ya Zhao , Qiang Zhang , Meilin Jin

Feline interferon-ω2 (FeIFN-ω2) holds potential as a therapeutic agent against feline viral infections. However, its clinical application is limited by rapid clearance and suboptimal antiviral effectiveness. Thus, in this study, an Fc-fused construct, FeIFN-ω2-Fc, was engineered to improve antiviral potency and pharmacokinetic properties both in vitro and in vivo. Three recombinant constructs—native FeIFN-ω2, FeIFN-ω2-Dimer, and FeIFN-ω2-Fc—were expressed in Chinese Hamster Ovary cells. All showed strong antiviral activity (10^6.74–10^8.42 IU/mg) and effectively activated downstream interferon signaling. Functional assays, including 50 % tissue culture infectious dose assay, quantitative polymerase chain reaction, and immunofluorescence, confirmed their ability to inhibit feline calicivirus (FCV), feline herpesvirus type 1 (FHV-1), and feline parvovirus (FPV). Glycosylation analysis revealed two sites (S102 and T128) in the ω2 domain of FeIFN-ω2-Fc that contributed to its structural stability and functional enhancement. Among the three candidates, FeIFN-ω2-Fc demonstrated the best overall profile, with higher expression levels, simplified purification, and favorable pharmacokinetics. In animal models, it was well tolerated and significantly alleviated clinical symptoms, reduced viral loads, and preserved tissue integrity following FHV-1 infection. Pharmacokinetic studies showed a marked increase in plasma half-life, from 5.80 ± 1.75 h for the native protein to 34.05 ± 6.36 h for the Fc-fused form. Further extension to 40.55 ± 6.61 h was achieved by introducing YTE mutations (S250Y/S252T/T254E) within the Fc region. Based on these findings, a dosing regimen of 4 × 10⁵ IU/kg every other day is proposed, supporting FeIFN-ω2-Fc as a strong candidate for feline antiviral therapy.

猫干扰素-ω - 2 （FeIFN-ω - 2）具有治疗猫病毒感染的潜力。然而，其临床应用受到快速清除和非最佳抗病毒效果的限制。因此，在本研究中，我们设计了一种fc融合构建物FeIFN-ω2-Fc，以提高体外和体内的抗病毒效力和药代动力学特性。在中国仓鼠卵巢细胞中表达了FeIFN-ω - 2、FeIFN-ω - 2-二聚体和FeIFN-ω - 2- fc三种重组结构。所有药物均表现出较强的抗病毒活性（106.74 ~ 108.42 IU/mg），并有效激活下游干扰素信号。功能试验，包括50%组织培养感染剂量试验、定量聚合酶链反应和免疫荧光，证实了它们抑制猫杯状病毒（FCV）、猫疱疹病毒1型（FHV-1）和猫细小病毒（FPV）的能力。糖基化分析发现FeIFN-ω2-Fc的ω2域有两个位点（S102和T128），这两个位点有助于其结构稳定性和功能增强。其中，FeIFN-ω - 2- fc具有较高的表达水平、纯化过程简化、良好的药代动力学等特点。在动物模型中，它耐受性良好，显著缓解了FHV-1感染后的临床症状，降低了病毒载量，并保持了组织完整性。药代动力学研究显示血浆半衰期明显增加，从天然蛋白的5.80±1.75小时增加到fc融合形式的34.05±6.36小时。通过在Fc区引入YTE突变（S250Y/S252T/T254E），进一步延长至40.55±6.61 h。基于这些发现，建议每隔一天4 × 105 IU/kg的给药方案，支持FeIFN-ω - 2- fc作为猫抗病毒治疗的强有力候选者。

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引用次数: 0

Structural determinants of nervous system exposure of adibelivir (IM-250) and related herpes helicase-primase inhibitors across animal species 神经系统暴露的结构决定因素adibelivir （IM-250）和相关的疱疹解旋酶启动酶抑制剂在动物物种。

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-09-03 DOI: 10.1016/j.antiviral.2025.106271

Christian Gege, Thomas Hoffmann, Gerald Kleymann

The high incidence and prevalence of herpes infections pose a significant health burden worldwide. Herpes simplex virus infections are the cause of herpes labialis, genital herpes or herpes keratitis and in rare cases life-threatening herpes encephalitis, meningitis or disseminated disease. After primary infection, herpes simplex viruses (HSVes) establish latency in the trigeminal and sacral ganglia and at least 30 % of patients experience clinically manifestant recurrences for life. For effective treatment of these neurotrophic HSVes, adequate drug exposure in the nervous system is essential.

Here we report the post administration exposure of structurally different helicase-primase inhibitors (HPIs) in plasma, blood, organs and, in particular, the nervous system of animals by HPLC/MS. In diverse animal species, after single or multiple doses of helicase-primase drugs by oral or intravenous administration, only adibelivir (IM-250) achieved concentrations in the nervous system in the range of plasma or blood levels (ratio 0.5 to 4 nervous system/plasma), while other helicase-primase inhibitors with distinct structures, including amenamevir, pritelivir or ABI-5366, showed a low brain/plasma ratio of less than 0.1. The efficient passage of helicase-primase drugs through the blood-brain and blood-nerve barrier is based on their distinct structure and chemical properties. In preclinical studies published so far, adibelivir was efficacious in the herpes encephalitis and neonatal animal model and reduced the reactivation competence of the neuronal latent herpes viral reservoir. Ongoing clinical trials with HPIs will show whether sufficient drug exposure in brain and ganglia will translate into more effective herpes therapies for patients.

疱疹感染的高发病率和流行率在世界范围内构成了重大的健康负担。单纯疱疹病毒感染会引起唇疱疹、生殖器疱疹或角膜炎，在极少数情况下还会引起危及生命的疱疹性脑炎、脑膜炎或播散性疾病。原发性感染后，单纯疱疹病毒（HSVes）在三叉神经节和骶神经节建立潜伏期，至少30%的患者经历临床明显的复发。为了有效治疗这些神经营养性HSVes，在神经系统中充分的药物暴露是必不可少的。在这里，我们报告了结构不同的解旋酶引物酶抑制剂（hpi）在给药后暴露于血浆、血液、器官，特别是神经系统中的HPLC/MS。在多种动物中，单次或多次口服或静脉给药解旋酶引物酶药物后，只有adibelivir （IM-250）在神经系统中的浓度达到血浆或血液水平范围内（神经系统/血浆的比率为0.5至4），而其他结构不同的解旋酶引物酶抑制剂，包括阿莫那韦、priitelivir或ABI-5366，其脑/血浆的比率低于0.1。解旋酶引物酶药物有效通过血脑和血神经屏障是基于它们独特的结构和化学性质。在目前发表的临床前研究中，阿迪贝利韦在疱疹脑炎和新生儿动物模型中有效，并降低了神经元潜伏疱疹病毒库的再激活能力。正在进行的hpi临床试验将显示在大脑和神经节中充分的药物暴露是否会转化为对患者更有效的疱疹治疗。

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引用次数: 0

DMBT1 promotes SARS-CoV-2 infection and its SRCR-derived peptide inhibits SARS-CoV-2 infection DMBT1促进SARS-CoV-2感染，其srcr衍生肽抑制SARS-CoV-2感染。

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-09-03 DOI: 10.1016/j.antiviral.2025.106269

Chenxi Zhu , Ziqiao Wang , Zhendong Pan , Xinjia Mai , Yiyun Chen , Wen Zhang , Ping Zhao , Hailin Tang , Rong Zhang , Dapeng Zhou

DMBT1 is a large scavenger receptor cysteine rich (SRCR) B protein that has been reported as a tumor suppressor gene and a co-receptor for HIV-1 infection. Here, we found DMBT1 is a major mucosal protein bound to SARS-CoV-2. Overexpression of DMBT1 in 293T cells may enhanced infection by SARS-CoV-2 in ACE2 dependent manner. Blocking experiments using overlapping peptide library of SRCR domain of DMBT1 showed that peptide 7 (CQGRVEVLYRGSWGTV), which contains bacteria-binding VEVLXXXXW motif, could inhibit SARS-CoV-2 infection. High concentration of peptide 7 can significantly inhibit the replication of SARS-CoV-2 in hamsters. Peptide 7 inhibits SARS-CoV-2 infection by aggregating the spike protein, thereby reducing its binding to and internalization by host cells. The cysteine residue at the N-terminus of peptide 7 is critical for dimerization and antiviral activity. These results indicate that DMBT1 can serve as a candidate target for the development of antiviral drugs.

DMBT1是一种富含半胱氨酸的大清道夫受体（SRCR） B蛋白，已被报道为肿瘤抑制基因和HIV-1感染的共受体。在这里，我们发现DMBT1是与SARS-CoV-2结合的主要粘膜蛋白。293T细胞中DMBT1的过表达可能以ACE2依赖的方式增强SARS-CoV-2感染。利用DMBT1 SRCR结构域重叠肽文库的阻断实验表明，含有细菌结合的VEVLXXXXW基序的肽7 （CQGRVEVLYRGSWGTV）可抑制SARS-CoV-2感染。高浓度肽7能显著抑制SARS-CoV-2在仓鼠体内的复制。肽7通过聚集刺突蛋白抑制SARS-CoV-2感染，从而减少其与宿主细胞的结合和内化。肽7 n端的半胱氨酸残基对二聚化和抗病毒活性至关重要。这些结果表明，DMBT1可以作为开发抗病毒药物的候选靶点。

引用次数: 0

Ensitrelvir suppresses prolonged olfactory abnormalities derived from SARS-CoV-2 infection in hamsters 恩司替韦抑制仓鼠SARS-CoV-2感染引起的长时间嗅觉异常。

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-09-02 DOI: 10.1016/j.antiviral.2025.106270

Ryoichi Tashima, Takayuki Kuroda, Haruaki Nobori, Satoshi Miyagawa, Takuya Yamane, Alice Shimba, Masaaki Nakashima, Keita Fukao

Ensitrelvir, an oral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CL protease inhibitor, is reportedly effective in suppressing smell disorder onset, a post-coronavirus disease 2019 (COVID-19) condition symptom. However, the pathogenesis of post-COVID-19 condition symptoms and the mechanism underlying the onset-suppressive effect of ensitrelvir are not fully understood. Here, we explored a post-COVID-19 condition model in hamsters 1 month post-SARS-CoV-2 infection and showed that ensitrelvir treatment caused early recovery of body weight, viral RNA suppression, and sense of smell improvement. In the nasal turbinates, SARS-CoV-2 was associated with significantly increased inflammatory markers, many of which were suppressed by ensitrelvir. Significant positive correlations were observed between smell testing and many inflammation-related markers in the nasal turbinates. In conclusion, our study indicates that chronic inflammation may occur in the nasal turbinates over a long period post-SARS-CoV-2 infection, leading to smell disorder onset in a hamster model. Early ensitrelvir treatment post-infection suppressed inflammation in the nasal turbinates and prevented smell disorder onset.

据报道，Ensitrelvir是一种口服严重急性呼吸综合征冠状病毒2 (SARS-CoV-2) 3CL蛋白酶抑制剂，可有效抑制2019年冠状病毒病（COVID-19）后症状嗅觉障碍的发作。然而，covid -19后症状的发病机制和ensitrelvir抑制发病作用的机制尚不完全清楚。在这里，我们探索了感染sars - cov -2后1个月的仓鼠后covid -19状态模型，结果表明，恩司替韦治疗可导致体重早期恢复、病毒RNA抑制和嗅觉改善。在鼻鼻甲中，SARS-CoV-2与炎症标志物显著增加相关，其中许多炎症标志物被恩司替韦抑制。嗅觉测试与鼻甲骨中许多炎症相关标志物之间观察到显著的正相关。总之，我们的研究表明，在sars - cov -2感染后的很长一段时间内，鼻甲可能会发生慢性炎症，导致仓鼠模型出现嗅觉障碍。感染后早期恩司替韦治疗可抑制鼻甲炎症，防止嗅觉障碍发作。

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引用次数: 0