Antiviral research最新文献_第7页

Optimization of the monoclonal antibody 3E1 through W32I mutation enhances antiviral efficacy against influenza virus subtypes H1N1 and H3N2 通过W32I突变优化单克隆抗体3E1增强抗病毒H1N1和H3N2亚型流感病毒的效果

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-08-15 DOI: 10.1016/j.antiviral.2025.106260

Shanshan Guan , Qingyu Wang , Jiaojiao Nie , Xin Yao , Kunpeng Xie , Weihao Zhao , Yaotian Chang , Lvzhou Zhu , Jiaru Hui , Tieyan Yin , Xiaopan Liu , Yingxin Zhang , Yaming Shan

The influenza virus has caused a global pandemic with significant morbidity and mortality, underscoring the need to optimize antibodies for improved antiviral efficacy. The monoclonal antibody 3E1 effectively neutralizes Group 1 influenza subtypes, H1 and H5, by inhibiting acid-induced conformational changes of hemagglutinin (HA). However, its neutralizing activity is relatively weak against the Group 2 subtype, H3. In order to broaden the neutralizing activity of wild-type 3E1 (3E1-WT) against both Group 1 and Group 2 viral strains, single-point mutants (3E1-L [W32I], 3E1-H [F103I]) and a double mutant (3E1-H + L [F103I, W32I]) were designed and generated in this study. The binding affinity, microneutralizing activity, and antiviral mechanisms of the mutants were evaluated in vitro. Notably, the 3E1-L mutant exhibited significantly enhanced antiviral activity against H1N1 and H3N2 compared to 3E1-WT, inhibiting both viral entry and release. In vivo studies also indicate that 3E1-L significantly enhances both prophylactic and therapeutic efficacy against A/New-York/61/2015-CDC-LV16A (H1N1) and A/Hong Kong/17/2014/8296 (H3N2). Molecular dynamics simulations of the 3E1-L/HA complex revealed that the W32I mutation could reduce steric hindrance between tryptophan at position 32 and the complementarity-determining region L1 loop of HA. In conclusion, the W32I substitution enhances the antiviral activity of 3E1-WT, suggesting that the optimization of 3E1-L a promising strategy for the development of more effective influenza therapy and prevention.

流感病毒已引起全球大流行，发病率和死亡率都很高，因此需要优化抗体以提高抗病毒效果。单克隆抗体3E1通过抑制酸诱导的血凝素（HA）构象变化，有效中和1组流感亚型H1和H5。然而，它对第二组亚型H3的中和活性相对较弱。为了扩大野生型3E1 （3E1- wt）对第1组和第2组病毒株的中和活性，本研究设计并产生了单点突变体3E1-L [W32I]、3E1- h [F103I]和双点突变体3E1- h +L [F103I， W32I]。在体外对突变体的结合亲和力、微中和活性和抗病毒机制进行了评价。值得注意的是，与3E1-WT相比，3E1-L突变体对H1N1和H3N2的抗病毒活性显著增强，抑制了病毒的进入和释放。体内研究也表明，3E1-L对A/New-York/61/2015-CDC-LV16A （H1N1）和A/Hong Kong/17/2014/8296 （H3N2）的预防和治疗效果均有显著增强。3E1-L/HA复合物的分子动力学模拟表明，W32I突变可以降低32位色氨酸与HA互补决定区L1环之间的位阻。综上所述，W32I的替换增强了3E1-WT的抗病毒活性，这表明3E1-L的优化是开发更有效的流感治疗和预防的有希望的策略。

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引用次数: 0

First evidence of efficacy of peptides targeting the pUL56-pUL89 interaction domain of the human cytomegalovirus terminase complex 首个针对人巨细胞病毒终止酶复合物的pUL56-pUL89相互作用结构域的肽的有效性证据。

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-08-14 DOI: 10.1016/j.antiviral.2025.106259

Sarah Mafi , Jean-Luc Poyet , Sophie Alain , Gaëtan Ligat , Sébastien Hantz

Human cytomegalovirus (HCMV) is a major cause of morbidity in immunocompromised patients and the leading viral cause of congenital infection. The toxicity and emergence of resistance associated with current antivirals underscore the need for alternative therapeutic strategies. The viral terminase complex (pUL56-pUL89-pUL51), essential for genome cleavage and packaging and without homologs in mammalian cells, represents a promising antiviral target. This study evaluated the antiviral potential of peptides targeting the pUL56–pUL89 interaction domain. Peptides derived from the minimal interaction domain between pUL56 and pUL89 (WF10: ₆₇₁WMVVKYMGFF₆₈₀) or an extended sequence (PD17: ₆₆₈PSEWMVVKYMGFFNFSD₆₈₄) were synthesized to interfere with this interaction. To optimize intracellular delivery, peptides were conjugated to a cell-penetrating peptide (CPP) derived from either the HIV-1 transactivator of transcription (TAT) or the Antennapedia homeodomain of Drosophila melanogaster (penetratin; PT). Peptide candidates- PT-WF10, TAT-WF10, and PT-PD17- were evaluated in cellular models for cytotoxicity, hemolysis, antiviral activity, and intracellular distribution. TAT-WF10 and PT-PD17 significantly reduced the cytopathic foci in HCMV-infected cells, with IC₅₀ values of 58 μM and 39 μM, respectively. PT-WF10 lacked antiviral activity, induced significant cytotoxicity and hemolysis, and was mainly localized in the cytoplasm, with only minimal nuclear signal. TAT-WF10 showed cytoplasmic and nuclear distribution, no hemolysis, but induced long-term cytotoxicity from 40 μM. PT-PD17 exhibited cytoplasmic and nuclear distribution, with no significant cytotoxicity or hemolysis up to 80 μM. This study provides the first proof of concept that a peptide targeting the pUL56–pUL89 interaction domain can inhibit HCMV replication. PT-PD17 demonstrated antiviral activity, intracellular distribution, and a favorable safety profile.

人巨细胞病毒（HCMV）是免疫功能低下患者发病的主要原因，也是先天性感染的主要病毒原因。与当前抗病毒药物相关的毒性和耐药性的出现强调了寻找替代治疗策略的必要性。病毒末端酶复合体（pUL56-pUL89-pUL51）在哺乳动物细胞中是基因组切割和包装所必需的，没有同源物，是一个很有前途的抗病毒靶点。本研究评估了靶向pUL56-pUL89相互作用结构域的肽的抗病毒潜力。从pUL56和pUL89之间的最小相互作用域（WF10: 671WMVVKYMGFF680）或扩展序列（PD17: 668PSEWMVVKYMGFFNFSD684）衍生的肽被合成来干扰这种相互作用。为了优化细胞内递送，将多肽偶联到细胞穿透肽（CPP）上，CPP来源于HIV-1转录反激活子（TAT）或果蝇触角同源结构域(penetratin；PT)。候选肽- PT-WF10、TAT-WF10和PT-PD17-在细胞模型中评估细胞毒性、溶血、抗病毒活性和细胞内分布。TAT-WF10和PT-PD17显著降低了hcmv感染细胞的病变灶，IC50值分别为58 μM和39 μM。PT-WF10缺乏抗病毒活性，具有明显的细胞毒性和溶血作用，主要存在于细胞质中，只有极少的核信号。TAT-WF10呈细胞质和细胞核分布，无溶血作用，但在40 μM下具有长期细胞毒性。PT-PD17呈细胞质和细胞核分布，在80 μM范围内无明显的细胞毒性和溶血作用。这项研究首次证明了靶向pUL56-pUL89相互作用结构域的肽可以抑制HCMV复制。PT-PD17表现出抗病毒活性、细胞内分布和良好的安全性。

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引用次数: 0

N-myristoyltransferase inhibitors as candidate broad-spectrum antivirals to treat viral infections promoted by immunosuppression associated with JAK inhibitors therapy n -肉豆蔻酰基转移酶抑制剂作为候选广谱抗病毒药物治疗与JAK抑制剂治疗相关的免疫抑制促进的病毒感染。

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-08-11 DOI: 10.1016/j.antiviral.2025.106258

Haydar Witwit, Juan C. de la Torre

The use of Janus kinase (JAK) inhibitors in the clinic has been expanded significantly during the last decade. However, the immunosuppressive effects of JAK inhibitors, via modulation of key innate cellular signaling pathways, can predispose treated patients to infections, and can also result in reduced control of silent infections and increased risk of reactivation of opportunistic infections. Thus, the JAK inhibitor ruxolitinib, approved for the treatment of myelofibrosis and polycythemia vera, has been shown to exerts a proviral activity during infection with different viruses. Therefore, the clinical relevance of developing antiviral treatments that can be effective in the presence of JAK inhibitors. N-terminal myristoyl transferase (NMT) inhibitors have been shown to exhibit potent antiviral activity against different viruses. Here we document that in the presence of ruxolitinib, NMT inhibitors retain their potent antiviral activity against different viruses, including HSV-1. Our findings support that NMT inhibitors should be explored as therapeutics to treat viral infections associated with immunosuppression caused by treatments with JAK inhibitors.

在过去的十年中，Janus激酶（JAK）抑制剂在临床中的应用已经显著扩大。然而，JAK抑制剂的免疫抑制作用，通过调节关键的先天细胞信号通路，可使接受治疗的患者易受感染，也可导致沉默感染的控制减少和机会性感染重新激活的风险增加。因此，被批准用于治疗骨髓纤维化和真性红细胞增多症的JAK抑制剂ruxolitinib已被证明在不同病毒感染期间发挥前病毒活性。因此，开发在存在JAK抑制剂的情况下有效的抗病毒治疗具有临床意义。n端肉豆蔻酰基转移酶（NMT）抑制剂已被证明对不同的病毒具有有效的抗病毒活性。在这里，我们证明在ruxolitinib的存在下，NMT抑制剂保留了对不同病毒（包括HSV-1）的有效抗病毒活性。我们的研究结果支持NMT抑制剂应该作为治疗JAK抑制剂治疗引起的免疫抑制相关病毒感染的治疗方法。

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引用次数: 0

The protease inhibitor Nirmatrelvir synergizes with inhibitors of GRP78 to suppress SARS-CoV-2 replication 蛋白酶抑制剂Nirmatrelvir与GRP78抑制剂协同抑制SARS-CoV-2复制。

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-07-29 DOI: 10.1016/j.antiviral.2025.106247

Doha Al Krad , Kim M. Stegmann , Antje Dickmanns , Priya Kumar , Claudia Blaurock , Björn-Patrick Mohl , Sina Jasmin Wille , Angele Breithaupt , Tobias Britzke , Anne Balkema-Buschmann , Matthias Dobbelstein

Nirmatrelvir, the active compound of the drug Paxlovid, inhibits the Main protease of SARS-CoV-2 (M^Pro, 3CL^Pro, NSP5). Its therapeutic application reduces but does not abolish the progression of COVID-19 in humans. Here we report a strong synergy of Nirmatrelvir with inhibitors of the ER chaperone GRP78 (HSPA5, BiP). Combining Nirmatrelvir with the GRP78-antagonizing drug candidate HA15 strongly inhibits the replication of SARS-CoV-2, to a far greater extent than either drug alone, as observed by diminished cytopathic effect, levels of detectable virus RNA, TCID₅₀ titers, and reduced accumulation of the non-structural proteins, as well as Spike and N proteins. The original SARS-CoV-2 strain as well as an Omicron variant were similarly susceptible towards the drug combination. Other GRP78 inhibitors or siRNAs targeting GRP78 also fortified the antiviral effect of Nirmatrelvir. In a hamster model of COVID-19, the combination of Nirmatrelvir with HA15 alleviated pneumonia-induced pulmonary atelectasis more effectively than the single drugs. In conclusion, inhibition of the virus Main protease and cellular GRP78 cooperatively diminishes virus replication and may improve COVID-19 therapy.

药物Paxlovid的活性化合物Nirmatrelvir抑制SARS-CoV-2的主要蛋白酶（MPro, 3CLPro, NSP5）。它的治疗应用减少但不能消除COVID-19在人类中的进展。在这里，我们报告了Nirmatrelvir与ER伴侣GRP78 （HSPA5, BiP）抑制剂的强协同作用。Nirmatrelvir与grp78拮抗候选药物HA15联合使用对SARS-CoV-2复制的抑制作用远远大于单独使用任何一种药物，这可以通过降低细胞病变效应、检测到的病毒RNA水平、TCID50滴度以及减少非结构蛋白、Spike和N蛋白的积累来观察到。最初的SARS-CoV-2菌株以及一种欧米克隆变体对这种药物组合同样敏感。其他GRP78抑制剂或靶向GRP78的sirna也增强了Nirmatrelvir的抗病毒作用。在新冠肺炎仓鼠模型中，Nirmatrelvir与HA15联合使用比单药更有效地缓解肺炎性肺不张。总之，抑制病毒主蛋白酶和细胞GRP78共同减少病毒复制，可能改善COVID-19治疗。

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引用次数: 0

Discovery of broad-spectrum antivirals targeting viral proteases using in silico structural modeling and cellular analysis 利用硅结构建模和细胞分析发现针对病毒蛋白酶的广谱抗病毒药物

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-07-29 DOI: 10.1016/j.antiviral.2025.106245

Dharmeshkumar Patel , Ramyani De , Niloufar Azadi , Sujin Lee , Savannah Shooter , Sarah Amichai , Shaoman Zhou , Danielle Monroe , Cameron Mahanke , Tamara R. McBrayer , Michael Muczynski , Abdullah Al-Homoudi , Joseph Engel , Yury A. Bochkov , James E. Gern , Ladislau C. Kovari , Franck Amblard , Raymond F. Schinazi

The development of broad-spectrum antivirals is a high-priority goal to prevent future global outbreaks. Some antiviral agents developed for specific viral protein targets may exhibit broad-spectrum antiviral activity or provide helpful information for broad-spectrum drug development. In this study, we compared the sequence- and structure-based similarity of SARS-CoV-2 3CL^pro with proteases from other viruses and identified 24 proteases with similar active-site structures. Our in-house lead molecules, NIP-22c and CIP-1 were reported as novel peptidomimetic, reversible covalent inhibitors of SARS-CoV-2 3CL^pro with nanomolar potency. Molecular docking of NIP-22c, CIP-1 and nirmatrelvir were performed with structurally similar proteases of different viruses, norovirus, enterovirus and rhinovirus. The predictions were validated with in vitro enzymatic and cell-based assays. As predicted, NIP-22c and CIP-1 showed broad-spectrum antiviral activity with EC₅₀ values in the nanomolar range against SARS-CoV-2, norovirus, enterovirus and rhinovirus by targeting 3CL/3C^pro. In contrast, nirmatrelvir did not show activity up to 10 μM against all three viruses and the mechanism of inactivity of nirmatrelvir was hypothesized through binding pocket analysis using molecular dynamics simulations.

开发广谱抗病毒药物是预防未来全球疫情的高度优先目标。一些针对特定病毒蛋白靶点开发的抗病毒药物可能表现出广谱抗病毒活性或为广谱药物开发提供有用的信息。在这项研究中，我们比较了SARS-CoV-2 3CLpro与其他病毒蛋白酶的序列和结构相似性，并鉴定出24种具有相似活性位点结构的蛋白酶。据报道，我们的内部铅分子NIP-22c和CIP-1是具有纳米级效力的新型肽类可逆性共价sars - cov - 23clpro抑制剂。将NIP-22c、CIP-1和nirmatrelvir与不同病毒（诺如病毒、肠病毒和鼻病毒）结构相似的蛋白酶进行分子对接。这些预测通过体外酶和细胞实验得到了验证。结果表明，NIP-22c和CIP-1对SARS-CoV-2、诺如病毒、肠道病毒和鼻病毒具有广谱抗病毒活性，EC50值在纳摩尔范围内。相比之下，nirmatrelvir对这三种病毒的活性均不超过10 μM，并通过分子动力学模拟的结合袋分析假设了nirmatrelvir无活性的机制。

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引用次数: 0

Suppression of herpes simplex virus type 1 replication by Pin1 inhibitors: insights from H-77 and novel compounds Pin1抑制剂抑制1型单纯疱疹病毒复制：来自H-77和新化合物的见解

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-07-25 DOI: 10.1016/j.antiviral.2025.106244

Abeer Mohamed Abdelfattah Elsayed , Miuko Kurose , Akifumi Higashiura , Akima Yamamoto , Toshihito Nomura , Takashi Irie , Masaya Fukushi , Jeffrey Encinas , Hisanaka Ito , Takayoshi Okabe , Tomoichiro Asano , Takemasa Sakaguchi

Herpes simplex virus type 1 (HSV-1) infection is widespread globally, necessitating the development of new therapeutic approaches. Previous studies have demonstrated that peptidyl-prolyl cis/trans isomerase Pin1 is essential for the replication of cytomegalovirus, a member of the herpesvirus family. Our research demonstrated that Pin1 knockdown significantly suppressed HSV-1 replication. Furthermore, we found that our Pin1 inhibitor H-77, along with four novel Pin1 inhibitors, also inhibited HSV-1 replication. The 50 % effective concentration (EC₅₀) of H-77 against HSV-1 replication in VeroE6 cells was 0.75 μM. In HSV-1-infected cells treated with H-77, expression levels of the immediate early viral protein ICP0 and late viral proteins VP5 and glycoprotein C (gC) were significantly reduced, indicating suppression of viral protein expression. Immunofluorescence staining revealed that in H-77-treated cells, viral proteins including VP5 were confined within the nucleus by an intact nuclear lamina. Transmission electron microscopy analysis demonstrated that H-77-treated cells exhibited markedly fewer extracellular viral particles, with nucleocapsid nuclear egress being inhibited. These results demonstrate that H-77 suppresses HSV-1 replication through dual mechanisms: inhibition of viral protein synthesis and blockade of nucleocapsid nuclear egress. These findings indicate that Pin1 represents a promising therapeutic target for HSV-1 inhibition, warranting further development of Pin1 inhibitors as anti-HSV-1 agents.

1型单纯疱疹病毒（HSV-1）感染在全球广泛存在，需要开发新的治疗方法。先前的研究表明，肽基脯氨酸顺/反式异构酶Pin1对巨细胞病毒（疱疹病毒家族的一员）的复制至关重要。我们的研究表明，Pin1敲低可显著抑制HSV-1复制。此外，我们发现我们的Pin1抑制剂H-77以及四种新的Pin1抑制剂也能抑制HSV-1的复制。H-77在VeroE6细胞中抑制HSV-1复制的50%有效浓度（EC50）为0.75 μM。在H-77处理的hsv -1感染细胞中，直接早期病毒蛋白ICP0和晚期病毒蛋白VP5和糖蛋白C （gC）的表达水平显著降低，表明病毒蛋白表达受到抑制。免疫荧光染色显示，在h -77处理的细胞中，包括VP5在内的病毒蛋白被完整的核层限制在细胞核内。透射电镜分析表明，h -77处理的细胞细胞外病毒颗粒明显减少，核衣壳核出口受到抑制。这些结果表明，H-77通过抑制病毒蛋白合成和阻断核衣壳核出口的双重机制抑制HSV-1的复制。这些发现表明，Pin1是抑制HSV-1的一个有希望的治疗靶点，需要进一步开发Pin1抑制剂作为抗HSV-1药物。

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引用次数: 0

Cerebrospinal fluid concentrations, viral suppression and biomarkers with long-acting cabotegravir and rilpivirine intramuscular injections 长效卡博特重力韦和利匹韦林肌肉注射的脑脊液浓度、病毒抑制和生物标志物。

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-07-23 DOI: 10.1016/j.antiviral.2025.106243

Aylin Yilmaz , Amedeo De Nicolò , Antonio D'Avolio , Magnus Gisslén

Our aim was to determine cerebrospinal fluid (CSF) and plasma concentrations of cabotegravir and rilpivirine (CAB/RPV) when administered as long-acting (LA) intramuscular injections every four (Q4W) or eight (Q8W) weeks, and to study the effect on viral suppression and CSF biomarkers of inflammation and neuronal injury. We included six adults with HIV receiving LA CAB/RPV Q4W or Q8W. CSF and plasma concentrations of CAB/RPV (15 samples) were analyzed by UHPLC-MS/MS. We also measured CSF and plasma HIV RNA, CSF and serum neopterin, CSF and serum β2-microglubulin, IgG index, albumin ratio, and CSF NfL. Median (range) total plasma cabotegravir concentrations were 1375 (963–2422) ng/mL, and in CSF 3.48 (1.47–7.60 ng/mL). For rilpivirine, concentrations were 93 (40–157) ng/mL and 1.21 (0.55–1.67) ng/mL, respectively. All participants hade CSF and plasma HIV RNA <20 copies/mL on every occasion. There were no significant changes in any of the CSF biomarkers in participants after switching to LA CAB/RPV. The combination of LA CAB/RPV can achieve therapeutic CSF concentrations throughout the dosing intervals and may suppress HIV replication in the CNS. No significant changes in CSF biomarkers of inflammation or neuronal injury were observed, indicating a neutral CNS effect.

我们的目的是测定cabotegravir和rilpivirine （CAB/RPV）作为长效（LA）肌肉注射每4周（Q4W）或8周（Q8W）给药时脑脊液（CSF）和血浆浓度，并研究对病毒抑制和脑脊液生物标志物炎症和神经元损伤的影响。我们纳入了6名接受LA CAB/RPV Q4W或Q8W治疗的成年HIV感染者。采用UHPLC-MS/MS对15例患者的脑脊液和血浆CAB/RPV浓度进行分析。同时测定脑脊液和血浆HIV RNA、脑脊液和血清neopterin、脑脊液和血清ß2-微球蛋白、IgG指数、白蛋白比值、脑脊液NfL。中位（范围）血浆cabote重力韦总浓度为1375 (963-2422)ng/mL， CSF中为3.48 （1.47-7.60 ng/mL）。利匹韦林的浓度分别为93 (40-157)ng/mL和1.21 (0.55-1.67)ng/mL。所有参与者每次都有CSF和血浆HIV RNA < 20拷贝/mL。转换到LA CAB/RPV后，参与者的任何CSF生物标志物均无显著变化。LA CAB/RPV联合使用可以在整个给药间隔内达到治疗性CSF浓度，并可能抑制HIV在中枢神经系统中的复制。脑脊液炎症或神经元损伤的生物标志物未见明显变化，表明中性中枢神经系统效应。

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引用次数: 0

Single-dose injection of human neutralizing antibody against ZIKV preserves male fertility and protects against lethal infection 单剂量注射人抗寨卡病毒中和抗体保护男性生育能力和预防致命感染。

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-07-22 DOI: 10.1016/j.antiviral.2025.106240

Hao Zhang , Ziyang Sheng , Feiyang Xue , Han Wang , Na Gao , Shiqi He , Yuetong Li , Dongying Fan , Peigang Wang , Lei Yu , Jing An

Zika virus (ZIKV) is a mosquito-transmitted flavivirus. Unlike other flavivirus members, ZIKV has a distinct tropism for the reproductive system. Previous studies have demonstrated that ZIKV has adverse impacts on the male reproductive system, particularly in testis and epididymis. However, no specific prophylactic and therapeutic agents are available against ZIKV till now. A human monoclonal antibody, 2B10, has been shown to be protective against microcephaly. Here, we intraperitoneally administered a single injection of 2B10 after ZIKV infection to explore its therapeutic potential on viral damage in testis and epididymis in both IFN-α/β and IFN-γ receptor-deficient (AG6) mouse and IFN-α/β receptor-deficient (A6) mouse models. The results showed that 2B10 significantly decreased the viremia and viral loads in organs in two types of male mice, markedly mitigated ZIKV-induced histo-morphologic disruption and inflammatory infiltration and maintained hormone levels. The integrity of tight junctions in the testis and epididymis was also maintained at normal levels by 2B10 administration. In long-term observation in ZIKV-infected A6 mice, 2B10 could confer effective protection of male fertility. In the AG6 model, 2B10 fully protected mice from lethal challenge. These results suggested that 2B10 provides effective protection in post-exposure therapy for ZIKV infection in mice. Since 2B10 is a human antibody, it might be a promising intervention candidate for maintaining male reproductive health during ZIKV infection in the endemic area.

寨卡病毒（ZIKV）是一种蚊子传播的黄病毒。与其他黄病毒成员不同，寨卡病毒对生殖系统有明显的倾向。以往的研究表明，寨卡病毒对男性生殖系统，特别是睾丸和附睾有不利影响。然而，目前尚无针对寨卡病毒的特异性预防和治疗药物。人单克隆抗体2B10已被证明对小头症有保护作用。本研究在ZIKV感染后腹腔单次注射2B10，探讨其对IFN-α/β和IFN-γ受体缺陷（AG6）小鼠和IFN-α/β受体缺陷（A6）小鼠模型睾丸和附睾病毒损伤的治疗潜力。结果表明，2B10可显著降低两种雄性小鼠器官内的病毒血症和病毒载量，显著减轻zikv诱导的组织形态学破坏和炎症浸润，维持激素水平。2B10给药后，睾丸和附睾紧密连接的完整性维持在正常水平。对感染zikv的A6小鼠进行长期观察，发现2B10能有效保护雄性生殖力。在AG6模型中，2B10完全保护小鼠免受致死攻击。这些结果提示2B10对小鼠寨卡病毒感染暴露后治疗具有有效的保护作用。由于2B10是一种人抗体，它可能是在寨卡病毒流行地区维持男性生殖健康的一种有希望的干预候选物。

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引用次数: 0

Mammalian-targeted antiviral peptide reduces dengue virus type 1 infection in Aedes aegypti 哺乳动物靶向抗病毒肽可减少埃及伊蚊中1型登革热病毒感染

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-07-21 DOI: 10.1016/j.antiviral.2025.106241

Danya Medina-Carrasco , Glay Chinea Santiago , Hilda Elisa Garay Pérez , Gladys Gutiérrez-Bugallo , Luis Gabriel González-Lodeiro , Anubis Vega-Rúa , Vivian Huerta Galindo

Dengue virus is the most important arbovirus for public health worldwide. Aedes aegypti is the DENV primary vector and acquires the virus during blood meal from a viremic human. BCN0941 is a structure-based designed antiviral peptide that inhibits early stages of DENV infection in mammalian cells [WO2015131858A2]. Studies of structure-activity relationship indicate that the molecular target of the antiviral activity of BCN0941 is the Low-density lipoprotein receptor related protein-1 (LRP1), an evolutionary conserved receptor that we have identified as putative DENV receptor in mammalian cells. In this work, we evaluated the antiviral activity of BCN0941 peptide against DENV serotype 1 in mosquito cells. In vitro assays were performed in cell lines C6/36 (Aedes albopictus) and Aag2 (Aedes aegypti). The antiviral activity in vivo in a metapopulation of field-collected A. aegypti mosquitoes was also evaluated. BCN0941 peptide exhibited the capacity to decrease viral infection in both experimental set up, in vivo and in vitro, up to a 50 % and 60 % of the treatment controls respectively, as determined by immunofluorescence. BCN0941 may be an effective DENV transmission-blocking drug due to its dual action in decreasing the viral load in infected people and the mosquito vector.

登革热病毒是全球公共卫生最重要的虫媒病毒。埃及伊蚊是登革热病毒的主要媒介，并在从病毒血症人的血液中获得病毒。BCN0941是一种基于结构设计的抗病毒肽，可抑制哺乳动物细胞早期DENV感染[WO2015131858A2]。构效关系研究表明，BCN0941抗病毒活性的分子靶点是低密度脂蛋白受体相关蛋白-1 (LRP1)，这是一种进化保守的受体，我们已经确定它可能是哺乳动物细胞中的DENV受体。在这项工作中，我们评估了BCN0941肽对蚊子细胞中DENV血清型1的抗病毒活性。体外检测细胞C6/36（白纹伊蚊）和Aag2（埃及伊蚊）。对野外采集的埃及伊蚊超种群体内抗病毒活性进行了评价。通过免疫荧光测定，BCN0941肽在体内和体外实验中均表现出减少病毒感染的能力，分别达到治疗对照组的50%和60%。BCN0941可能是一种有效的DENV传播阻断药物，具有降低感染者和蚊虫载体病毒载量的双重作用。

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引用次数: 0

High-throughput split-GFP antiviral screening assay against fusogenic paramyxoviruses 高通量分裂- gfp抗融合副粘病毒筛选试验。

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-07-21 DOI: 10.1016/j.antiviral.2025.106242

Laura Vandemaele , Thibault Francken , Joost Schepers , Winston Chiu , Niels Cremers , Hugo Klaassen , Charlène Marcadet , Lorena Sanchez Felipe , Arnaud Marchand , Patrick Chaltin , Pieter Leyssen , Johan Neyts , Manon Laporte

The paramyxovirus family includes important pathogens such as measles and mumps viruses, as well as emerging pathogens with pandemic potential such as Nipah virus. Despite the threat to public health and the frequent identification of novel paramyxoviruses, no antiviral drugs are currently available. A hallmark of most paramyxoviruses is the induction of cell-cell fusion leading to syncytia formation. To facilitate antiviral drug discovery, we leveraged this trait and established a high-throughput split-green fluorescent protein (GFP) antiviral screening assay suitable for high-content imaging through the quantification of virus-induced GFP⁺ syncytia. The assay was validated with well-known broad-spectrum antiviral compounds against representative members of five different Paramyxovirinae genera. Using this split-GFP assay, a small-molecule repurposing library of approximately 3000 compounds was screened against recombinant Cedar virus (CedV), a nonpathogenic henipavirus. Two molecules were identified: Cathepsin Inhibitor 1 with henipavirus-specific activity and PF-543 with pan-paramyxovirus activity. Both molecules inhibit viral replication by blocking cell-cell fusion. The split-GFP assay presented here will enable the development of extensive drug discovery initiatives aimed at identifying much-needed pan-henipavirus/paramyxovirus inhibitors.

副粘病毒家族包括麻疹和腮腺炎病毒等重要病原体，以及尼帕病毒等具有大流行潜力的新出现病原体。尽管对公共卫生构成威胁，并且经常发现新型副粘病毒，但目前尚无抗病毒药物可用。大多数副粘病毒的一个特点是诱导细胞-细胞融合导致合胞体的形成。为了促进抗病毒药物的发现，我们利用这一特性，通过对病毒诱导的GFP+合胞体的定量分析，建立了适用于高含量成像的高通量分裂绿色荧光蛋白（GFP）抗病毒筛选试验。该试验与众所周知的广谱抗病毒化合物对五个不同副粘病毒属的代表成员进行了验证。利用这种分裂- gfp试验，筛选了一个含有约3000种化合物的小分子重组文库，以对抗重组雪松病毒（一种非致病性亨尼帕病毒）。鉴定出两个分子：具有亨尼帕病毒特异性活性的组织蛋白酶抑制剂1和具有泛副粘病毒活性的PF-543。这两种分子都通过阻断细胞-细胞融合来抑制病毒复制。这里提出的分裂- gfp测定将使广泛的药物发现倡议的发展，旨在确定急需的泛亨尼帕病毒/副粘病毒抑制剂。

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引用次数: 0