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CXCR7 genetic variant predicts treatment response of pegylated-interferon α in HBeAg-positive chronic hepatitis B patients CXCR7 基因变异可预测 HBeAg 阳性慢性乙型肝炎患者对聚乙二醇干扰素 α 的治疗反应
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-10 DOI: 10.1016/j.antiviral.2024.106005
Mengqi Luo , Xinghe Liang , Bin Zhou , Jinlin Hou , De-Ke Jiang

Objectives

CXC chemokine receptor 7 (CXCR7) plays pivotal roles in different virus infections. However, no research focused on the role of CXCR7 in hepatitis B virus (HBV)-infected patients. The primary aim of this study is to elucidate the role of CXCR7 in predicting the treatment response of chronic hepatitis B (CHB) patients undergoing pegylated interferon-alpha (PegIFNα) therapy.

Methods

Two cohorts with a total of 945 Chinese CHB patients (Cohort 1, n = 238; Cohort 2, n = 707) were enrolled in this retrospective study, all the patients were positive for hepatitis B e antigen (HBeAg) and received PegIFNα treatment for 48 weeks and followed-up for 24 weeks post-treatment. Nineteen tag single-nucleotide polymorphisms (SNPs) were selected within and surrounding the CXCR7 gene region. The associations of CXCR7 SNPs and polygenic score (PGS) with PegIFNα treatment response were investigated in the two cohorts.

Results

Among the 19 candidate SNPs of CXCR7, rs2952665 (A > G) was significantly associated with combined response (CR, defined as HBeAg seroconversion and HBV DNA level <3.3log10IU/mL, P = 0.002) and hepatitis B surface antigen (HBsAg) decline (P = 0.015) in the two cohorts at week 72. Furthermore, a PGS comprising CXCR7_rs2952665 and five additional SNPs, which were previously recognized as biomarkers of PegIFNα treatment response, demonstrated a robust correlation with both CR (P = 1.38 × 10−12) and HBsAg decline (P = 0.003) in all the patients.

Conclusion

This research illustrated that CXCR7_rs2952665 is a promising predictor of the PegIFNα therapy efficiency in Chinese HBeAg-positive CHB patients. A PGS consisting of CXCR7_rs2952665 and five previously reported SNPs predicts treatment response to PegIFNα better.

目的CXC趋化因子受体 7(CXCR7)在不同的病毒感染中发挥着关键作用。然而,还没有研究关注 CXCR7 在乙型肝炎病毒(HBV)感染患者中的作用。本研究的主要目的是阐明 CXCR7 在预测接受聚乙二醇干扰素-α(PegIFNα)治疗的慢性乙型肝炎(CHB)患者的治疗反应中的作用。所有患者均为乙型肝炎e抗原(HBeAg)阳性,接受PegIFNα治疗48周,治疗后随访24周。研究人员在 CXCR7 基因区及其周围选择了 19 个标记单核苷酸多态性(SNPs)。在两个队列中调查了 CXCR7 SNPs 和多基因评分(PGS)与 PegIFNα 治疗反应的关系。结果在 CXCR7 的 19 个候选 SNPs 中,rs2952665 (A > G) 与两个队列在第 72 周时的合并应答(CR,定义为 HBeAg 血清转换和 HBV DNA 水平 <3.3log10IU/mL,P = 0.002)和乙肝表面抗原(HBsAg)下降(P = 0.015)显著相关。此外,由 CXCR7_rs2952665 和另外五个 SNPs 组成的 PGS 与所有患者的 CR(P = 1.38 × 10-12)和 HBsAg 下降(P = 0.003)都有很强的相关性。由 CXCR7_rs2952665 和之前报道的五个 SNPs 组成的 PGS 能更好地预测 PegIFNα 的治疗反应。
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引用次数: 0
MβCD inhibits SFTSV entry by disrupting lipid raft structure of the host cells MβCD 通过破坏宿主细胞的脂质筏结构抑制 SFTSV 的进入
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-10 DOI: 10.1016/j.antiviral.2024.106004
Min Cheng , Rui Zhang , Jianshu Li , Wenyuan Ma , Linrun Li , Na Jiang , Bingxin Liu , Jing Wu , Nan Zheng , Zhiwei Wu

Severe fever with thrombocytopenia syndrome virus (SFTSV), recently named as Dabie bandavirus, belongs to the family Phenuiviridae of the order Bunyavirales, is a newly-identified bunyavirus with a case fatality rate of up to 30%, posing a serious threat to public health. Lipid rafts on plasm membranes are important for the entry of enveloped viruses; however, the role of lipid rafts in bunyavirus entry remains unclear. In this study, we found that methyl-beta-cyclodextrin (MβCD), a drug that disrupts cholesterol in lipid rafts of cell membranes, inhibits SFTSV infection. Additionally, there is a back-complementary effect of SFTSV infection upon the addition of cholesterol. Moreover, the concentration of SFTSV particles in lipid rafts during entry directly indicated the role of lipid rafts as a gateway, whereas MβCD could inhibit SFTSV entry by affecting the structure of lipid rafts. In an in vivo study, MβCD also reduced the susceptibility of mice to SFTSV infection. Our results suggest that SFTSV can interact with Talin1 proteins on lipid rafts to enter host cells by endocytosis of lipid rafts and reveal the potential therapeutic value of MβCD for SFTSV infection.

严重发热伴血小板减少综合征病毒(SFTSV)最近被命名为达比带状疱疹病毒,属于布尼亚病毒科布尼亚病毒属,是一种新发现的布尼亚病毒,病死率高达30%,对公共卫生构成严重威胁。质膜上的脂质筏对包膜病毒的进入非常重要,但脂质筏在布尼亚病毒进入中的作用仍不清楚。在这项研究中,我们发现甲基-β-环糊精(MβCD)这种能破坏细胞膜脂质筏中胆固醇的药物能抑制 SFTSV 的感染。此外,加入胆固醇后,SFTSV 的感染会出现反补效应。此外,SFTSV 颗粒在进入过程中在脂质筏中的浓度直接表明了脂质筏作为网关的作用,而 MβCD 可以通过影响脂质筏的结构来抑制 SFTSV 的进入。在一项体内研究中,MβCD还降低了小鼠对SFTSV感染的易感性。我们的研究结果表明,SFTSV能与脂质筏上的Talin1蛋白相互作用,通过脂质筏的内吞作用进入宿主细胞,并揭示了MβCD对SFTSV感染的潜在治疗价值。
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引用次数: 0
Bithiazole inhibitors of PI4KB show broad-spectrum antiviral activity against different viral families PI4KB 双噻唑抑制剂对不同病毒科具有广谱抗病毒活性
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-10 DOI: 10.1016/j.antiviral.2024.106003
Maria Grazia Martina , Vincent Carlen , Sarah Van der Reysen , Elena Bianchi , Noemi Cabella , Emmanuele Crespan , Marco Radi , Valeria Cagno

Broad-spectrum antivirals can be extremely important for pandemic preparedness. Targeting host factors dispensable for the host but indispensable for the virus can result in high barrier to resistance and a large range of viruses targeted. PI4KB is a lipid kinase involved in the replication of several RNA viruses, but common inhibitors of this target are mainly active against members of the Picornaviridae family. Herein we describe the optimization of bithiazole PI4KB inhibitors as broad-spectrum antivirals (BSAs) active against different members of the Picornaviridae, Coronaviridae, Flaviviridae and Poxviridae families. Since some of these viruses are transmitted via respiratory route, the efficacy of one of the most promising compounds was evaluated in an airway model. The molecule showed complete viral inhibition and absence of toxicity. These results pave the road for the development of new BSAs.

广谱抗病毒药物对防范大流行病极为重要。针对对宿主来说可有可无但对病毒来说不可或缺的宿主因子,可以产生很高的抗药性屏障,并能针对多种病毒。PI4KB 是一种脂质激酶,参与了多种 RNA 病毒的复制,但针对这一靶点的常见抑制剂主要对 Picornaviridae 家族成员有效。在本文中,我们介绍了双噻唑类 PI4KB 抑制剂作为广谱抗病毒药物(BSAs)的优化情况,这些药物对 Picornaviridae、Coronaviridae、Flaviviridae 和 Poxviridae 家族的不同成员都有活性。由于其中一些病毒通过呼吸道传播,因此在气道模型中对其中一种最有前景的化合物进行了药效评估。该分子对病毒有完全抑制作用,且无毒性。这些结果为开发新的 BSA 铺平了道路。
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引用次数: 0
Treatment efficacy of cidofovir and brincidofovir against clade II Monkeypox virus isolates 西多福韦和布林昔多福韦对第二型猴痘病毒分离株的治疗效果。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-05 DOI: 10.1016/j.antiviral.2024.105995
Jérémie Prévost , Angela Sloan , Yvon Deschambault , Nikesh Tailor , Kevin Tierney , Kimberly Azaransky , Srinivas Kammanadiminti , Douglas Barker , Shantha Kodihalli , David Safronetz

While historically confined to endemic areas, Monkeypox virus (MPXV) infection has increasingly garnered international attention due to sporadic outbreaks in non-endemic countries in the last two decades and its potential for human-to-human transmission. In 2022, a multi-country outbreak of mpox disease was declared by the World Health Organization (WHO) and nearly 100 000 mpox cases have been reported since the beginning of this pandemic. The clade II variant of the virus appears to be responsible for the vast majority of these infections. While there are no antiviral drugs currently approved to treat mpox specifically, the use of tecovirimat (TPOXX®) and brincidofovir (Tembexa®) is recommended by the Centers for Disease Control and Prevention (CDC) for compassionate use in severe mpox cases, since both are FDA-approved for the treatment of the closely related smallpox disease. Given the emergence of multiple tecovirimat-resistant infections, we aimed to evaluate the treatment efficacy of brincidofovir and its active compound, cidofovir, against MPXV clade II strains. Following intranasal infection, we show that cidofovir and brincidofovir can strongly reduce the viral replication of MPXV clade IIa and IIb viruses in the respiratory tract of susceptible mice when administered systemically and orally, respectively. The high antiviral activity of both compounds against historical and currently circulating MPXV strains supports their therapeutic potential for clinical application.

猴痘病毒(MPXV)感染虽然历来仅限于流行地区,但由于过去二十年来在非流行国家零星爆发,并有可能在人际间传播,因此日益引起国际关注。2022 年,世界卫生组织(WHO)宣布多国爆发 mpox 疾病,自这次大流行开始以来,已报告了近 10 万个 mpox 病例。在这些感染病例中,绝大多数似乎是由该病毒的支系 II 变体引起的。虽然目前还没有专门用于治疗天花的抗病毒药物获得批准,但美国疾病控制和预防中心(CDC)建议对严重的天花病例使用替考韦瑞(TPOXX®)和布林昔多韦(Tembexa®),因为这两种药物都已获得美国食品及药物管理局批准用于治疗密切相关的天花疾病。鉴于出现了多种对替考韦酯耐药的感染,我们旨在评估布林昔多韦及其活性化合物西多福韦对 MPXV 支系 II 菌株的治疗效果。结果表明,经鼻内感染后,西多福韦和布林昔多福韦在全身给药和口服给药的情况下,可分别显著降低易感小鼠呼吸道中 MPXV IIa 和 IIb 类病毒的复制。这两种化合物对历史上和目前流行的 MPXV 病毒株具有很高的抗病毒活性,这支持了它们在临床应用中的治疗潜力。
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引用次数: 0
Dynamic features of virus protein 1 and substitutions in the 3-phenyl ring determine the potency and broad-spectrum activity of capsid-binding pyrazolo[3,4-d]pyrimidines against rhinoviruses 病毒蛋白 1 的动态特征和 3-苯基环的取代决定了与囊膜结合的吡唑并[3,4-d]嘧啶对鼻病毒的效力和广谱活性。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-03 DOI: 10.1016/j.antiviral.2024.105993
Martina Richter , Maria Khrenova , Elena Kazakova , Olga Riabova , Anna Egorova , Vadim Makarov , Michaela Schmidtke

Pyrazolo[3,4-d]pyrimidines represent one potent class of well tolerated and highly active rhinovirus (RV) inhibitors that act as capsid binders. The lead compound OBR-5-340 inhibits a broad-spectrum of RVs. Aiming to improve lead activity, we evaluated the impact of structural modifications in the 3-phenyl ring of OBR-5-340 on its potency and spectrum of anti-RV activity vitro. Our results demonstrate the crucial role of substitution at position 4 for strong, broad-spectrum anti-RV activity. The 4-methyl (RCB23137) and 4-chloro (RCB23138) derivatives outperformed OBR-5-340 in terms of potency and anti-RV activity spectrum. Based on these findings, the compounds were selected for computational binding studies. Molecular dynamic simulations with six RVs differing in OBR-5-340, RCB23137, and RCB23138 sensitivity proved the impact of dynamic features of two VP1 loops enveloping these inhibitors on antiviral potency.

吡唑并[3,4-d]嘧啶类化合物是一类耐受性好、活性高的鼻病毒(RV)抑制剂,可作为病毒盖粘合剂。先导化合物 OBR-5-340 可抑制多种鼻病毒。为了提高先导化合物的活性,我们评估了 OBR-5-340 的 3 苯环结构修饰对其药效和体外抗 RV 活性谱的影响。我们的研究结果表明,第 4 位的取代对于强效、广谱的抗 RV 活性起着至关重要的作用。4-甲基(RCB23137)和 4-氯(RCB23138)衍生物在药效和抗 RV 活性谱方面优于 OBR-5-340。基于这些发现,我们选择了这些化合物进行计算结合研究。用六种对 OBR-5-340、RCB23137 和 RCB23138 敏感性不同的 RV 进行分子动力学模拟,证明了包覆这些抑制剂的两个 VP1 环的动态特征对抗病毒效力的影响。
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引用次数: 0
The triple combination of Remdesivir (GS-441524), Molnupiravir and Ribavirin is highly efficient in inhibiting coronavirus replication in human nasal airway epithelial cell cultures and in a hamster infection model 雷米替韦(GS-441524)、莫诺吡拉韦和利巴韦林的三联疗法能高效抑制冠状病毒在人鼻气道上皮细胞培养物和仓鼠感染模型中的复制。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-03 DOI: 10.1016/j.antiviral.2024.105994
Thuc Nguyen Dan Do , Rana Abdelnabi , Bernadett Boda , Samuel Constant , Johan Neyts , Dirk Jochmans

The use of fixed dose-combinations of antivirals with different mechanisms of action has proven key in the successful treatment of infections with HIV and HCV. For the treatment of infections with SARS-CoV-2 and possible future epi-/pandemic coronaviruses, it will be important to explore the efficacy of combinations of different drugs, in particular to avoid resistance development, such as in patients with immunodeficiencies. This work explores the effect of a combination of 3 broad-spectrum antiviral nucleosides on the replication of coronaviruses. To that end, we made use of primary human airway epithelial cell (HAEC) cultures grown at the air-liquid interface that were infected with the beta coronavirus OC43. We found that the triple combination of GS-441524 (the parent nucleoside of remdesivir), molnupiravir and ribavirin resulted in a more pronounced antiviral efficacy than what could be expected from a purely additive antiviral effect. The potency of this triple combination was next tested in SARS-CoV-2 infected hamsters in a prophylactic setup. To that end, for each of the drugs, intentionally suboptimal or even ineffective doses were selected. Yet, in the lungs of all hamsters that received triple prophylactic therapy (but not in those that received the respective double combinations) no infectious virus was detectable. Our findings indicate that co-administration of approved drugs for the treatment of coronavirus infections should be further explored but also against other families of viruses with epidemic and pandemic potential for which no effective antiviral treatment is available.

事实证明,使用具有不同作用机制的固定剂量组合抗病毒药物是成功治疗艾滋病毒和丙型肝炎病毒感染的关键。对于治疗 SARS-CoV-2 和未来可能出现的流行/大流行冠状病毒感染,探索不同药物组合的疗效将非常重要,特别是要避免耐药性的产生,例如免疫缺陷患者的耐药性。这项研究探讨了 3 种广谱抗病毒核苷类药物组合对冠状病毒复制的影响。为此,我们利用在气液界面生长的原代人气道上皮细胞(HAEC)培养物感染了β冠状病毒OC43。我们发现,GS-441524(雷米替韦的母体核苷)、molnupiravir 和利巴韦林的三重组合产生的抗病毒效果比纯粹的相加抗病毒效果更为显著。接下来,在预防性实验中,在感染了 SARS-CoV-2 的仓鼠身上测试了这种三联疗法的效力。为此,对每种药物都有意选择了次优甚至无效的剂量。然而,在所有接受三联预防治疗的仓鼠肺部(而不是接受相应双联预防治疗的仓鼠肺部)都检测不到传染性病毒。我们的研究结果表明,不仅应进一步探索联合使用已获批准的药物治疗冠状病毒感染的方法,而且还应探索联合使用其他具有流行和大流行潜力的病毒家族的方法,因为这些病毒目前还没有有效的抗病毒治疗方法。
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引用次数: 0
Coronavirus nucleocapsid-based vaccine provides partial protection against hetero-species coronavirus in murine models 基于冠状病毒核壳的疫苗可在小鼠模型中提供针对异种冠状病毒的部分保护。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-23 DOI: 10.1016/j.antiviral.2024.105991
Pureum Lee , Jihee Kim , Hanseul Oh , Chang-Ung Kim , Ahn Young Jeong , Moo-Seung Lee , Min Seong Jang , Jung Joo Hong , Jung-Eun Park , Doo-Jin Kim

Most coronavirus vaccines focus on the spike (S) antigen, but the frequent mutations in S raise concerns about the vaccine efficacy against new variants. Although additional antigens with conserved sequences are have been tested, the extent to which these vaccines can provide immunity against different coronavirus species remains unclear. In this study, we assessed the potential of nucleocapsid (N) as a coronavirus vaccine antigen. Immunization with MERS-CoV N induced robust immune responses, providing significant protection against MERS-CoV. Notably, MERS-CoV N elicited cross-reactive T cell responses to SARS-CoV-2 N and significantly reduced lung inflammation following a SARS-CoV-2 challenge in the transient hACE2 mouse model. However, in K18-hACE transgenic mice, the vaccine showed limited protection. Collectively, our findings suggest that coronavirus N can be an effective vaccine antigen against homologous viruses, but its efficacy may vary across different coronaviruses, highlighting the need for further research on pan-coronavirus vaccines using conserved antigens.

大多数冠状病毒疫苗都以尖峰(S)抗原为重点,但 S 抗原的频繁变异令人担忧疫苗对新变种的免疫效果。尽管已经对其他具有保守序列的抗原进行了测试,但这些疫苗能在多大程度上提供针对不同冠状病毒物种的免疫力仍不清楚。在本研究中,我们评估了核壳(N)作为冠状病毒疫苗抗原的潜力。用MERS-CoV N免疫可诱导强有力的免疫反应,提供针对MERS-CoV的显著保护。值得注意的是,在瞬时 hACE2 小鼠模型中,MERS-CoV N 可引起与 SARS-CoV-2 N 交叉反应的 T 细胞应答,并显著减轻 SARS-CoV-2 挑战后的肺部炎症。然而,在 K18-hACE 转基因小鼠中,疫苗显示出有限的保护作用。总之,我们的研究结果表明,冠状病毒 N 可以作为一种有效的疫苗抗原来对抗同源病毒,但其功效在不同的冠状病毒中可能会有所不同,这凸显了利用保守抗原进一步研究泛冠状病毒疫苗的必要性。
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引用次数: 0
Anti-SARS-CoV-2 gapmer antisense oligonucleotides targeting the main protease region of viral RNA 针对病毒 RNA 主要蛋白酶区的抗 SARS-CoV-2 gapmer 反义寡核苷酸。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-23 DOI: 10.1016/j.antiviral.2024.105992
Masako Yamasaki , Wakana Saso , Takuya Yamamoto , Masayoshi Sato , Hiroko Takagi , Tetsuya Hasegawa , Yuji Kozakura , Hiroyuki Yokoi , Hirofumi Ohashi , Kana Tsuchimoto , Rina Hashimoto , Shuetsu Fukushi , Akihiko Uda , Masamichi Muramatsu , Kazuo Takayama , Ken Maeda , Yoshimasa Takahashi , Tsuyoshi Nagase , Koichi Watashi

Given the worldwide risk for the outbreak of emerging/re-emerging respiratory viruses, establishment of new antiviral strategies is greatly demanded. In this study, we present a scheme to identify gapmer antisense oligonucleotides (ASOs) targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA that efficiently inhibit viral replication. We synthesized approximately 300 gapmer ASOs designed to target various SARS-CoV-2 RNA regions and evaluated their activity in cell-based assays. Through a multistep screening in cell culture systems, we identified that ASO#41, targeting the coding region for viral main protease, reduced SARS-CoV-2 RNA levels in infected cells and inhibited virus-induced cytopathic effects. Antiviral effect of ASO#41 was also observed in iPS cell-derived human lung organoids. ASO#41 depleted intracellular viral RNAs during genome replication in an endogenous RNaseH-dependent manner. ASO#41 showed a wide range of antiviral activity against SARS-CoV-2 variants of concern including Alpha, Delta, and Omicron. Intranasal administration to mice exhibited intracellular accumulation of ASO#41 in the lung and significantly reduced the viral infectious titer, with milder body weight loss due to SARS-CoV-2 infection. Further chemical modification with phosphoryl guanidine-containing backbone linkages provided an elevation of anti-SARS-CoV-2 activity, with 23.4 nM of 50% antiviral inhibitory concentration, one of the strongest anti-SARS-CoV-2 ASOs reported so far. Our study presents an approach to identify active ASOs against SARS-CoV-2, which is potentially useful for establishing an antiviral strategy by targeting genome RNA of respiratory viruses.

鉴于新发/再发呼吸道病毒在全球范围内爆发的风险,建立新的抗病毒策略是非常必要的。在本研究中,我们提出了一种方案,以识别能有效抑制病毒复制的、靶向严重急性呼吸系统综合征冠状病毒 2(SARS-CoV-2)RNA 的间隙反义寡核苷酸(ASO)。我们合成了约 300 种针对不同 SARS-CoV-2 RNA 区域设计的间隙聚合物 ASO,并在基于细胞的试验中评估了它们的活性。通过在细胞培养系统中进行多步筛选,我们发现针对病毒主蛋白酶编码区的 ASO#41 能降低感染细胞中的 SARS-CoV-2 RNA 水平,并抑制病毒诱导的细胞病理效应。在 iPS 细胞衍生的人肺器官组织中也观察到了 ASO#41 的抗病毒作用。在基因组复制过程中,ASO#41 以内源性 RNaseH 依赖性方式消耗细胞内病毒 RNA。ASO#41 对包括 Alpha、Delta 和 Omicron 在内的 SARS-CoV-2 变体具有广泛的抗病毒活性。小鼠经鼻给药后,ASO#41 会在肺部细胞内蓄积,并显著降低病毒感染滴度,同时减轻 SARS-CoV-2 感染导致的体重减轻。通过含磷酸胍骨架连接的进一步化学修饰,提高了抗 SARS-CoV-2 的活性,50% 的抗病毒抑制浓度为 23.4 nM,是迄今报道的最强抗 SARS-CoV-2 ASO 之一。我们的研究提出了一种鉴别抗 SARS-CoV-2 活性 ASO 的方法,它可能有助于通过靶向呼吸道病毒的基因组 RNA 建立抗病毒策略。
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引用次数: 0
Import of extracellular 2′-3′cGAMP by the folate transporter, SLC19A1, establishes an antiviral response that limits herpes simplex virus-1 叶酸转运体 SLC19A1 导入细胞外 2'-3'cGAMP 可建立抗病毒反应,限制单纯疱疹病毒-1。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-21 DOI: 10.1016/j.antiviral.2024.105989
Zsuzsa K. Szemere, Eain A. Murphy

Recently it was discovered that extracellular 2′-3′cGAMP can activate the STING pathway in a cGAS-independent fashion by being transported across the cell membrane via the folate transporter, SLC19A1, the first identified extracellular antiporter of this critical signaling molecule in cancer cells. We hypothesized that this non-canonical activation of STING pathway would function to establish an antiviral state similar to that seen with the paracrine antiviral activities of interferon. Herein, we report that treatment of the monocytic cell line, THP-1 cells and SH-SY5Y neuronal cell line with exogenous 2′-3′cGAMP induces interferon production and establishes an antiviral state that limits herpes simplex virus-1 (HSV-1), a ubiquitous virus with high seropositivity in the human population. Using either pharmaceutical inhibition or genetic knockout of SLC19A1 blocks the 2′-3′cGAMP-induced inhibition of viral replication. Our data indicate SLC19A1 functions as a newly identified antiviral mediator for extracellular 2′-3′cGAMP. This work presents novel and important findings about an antiviral mechanism which information could aid in the development of better antiviral drugs in the future.

最近发现,细胞外的 2'-3'cGAMP 可通过叶酸转运体 SLC19A1 跨细胞膜转运,以一种不依赖于 cGAS 的方式激活 STING 通路。我们假设 STING 通路的这种非经典激活功能将建立一种抗病毒状态,类似于干扰素的旁分泌抗病毒活性。在此,我们报告了用外源 2'-3'cGAMP 处理单核细胞系、THP-1 细胞和 SH-SY5Y 神经元细胞系可诱导干扰素产生,并建立一种限制单纯疱疹病毒-1(HSV-1)的抗病毒状态。使用药物抑制或基因敲除 SLC19A1 可阻止 2'-3'cGAMP 诱导的病毒复制抑制。我们的数据表明,SLC19A1 是一种新发现的细胞外 2'-3'cGAMP 抗病毒介质。这项工作提供了有关抗病毒机制的新颖而重要的发现,这些信息有助于将来开发更好的抗病毒药物。
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引用次数: 0
A novel live DNA tagging system for African swine fever virus shows that bisbenzimide Hoechst 33342 can effectively block its replication 一种新型非洲猪瘟病毒活 DNA 标记系统显示,双苯亚胺 Hoechst 33342 能有效阻断非洲猪瘟病毒的复制
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-19 DOI: 10.1016/j.antiviral.2024.105973
Veronica Martin , Beatriz Guerra , Bruno Hernaez , Sandrine Kappler-Gratias , Franck Gallardo , Milagros Guerra , German Andres , Ali Alejo

African swine fever virus (ASFV) infection causes a frequently fatal disease in domestic swine that has affected more than 50 countries worldwide since 2021, with a major impact on animal welfare and economy. The development of effective vaccines or antivirals against this disease are urgently required for its effective control. Live detection of viral replication has been used as a tool for the screening and characterization of antiviral compounds in other dsDNA genome containing viruses. Here, we have adapted the ANCHOR fluorescent DNA labelling system to ASFV by constructing and characterizing a novel recombinant virus. We show that this virus is viable and effectively tags viral DNA replication sites, which can be detected and quantified in real time. Further, we have used high content cell microscopy to test the antiviral activity of bisbenzimide compounds and show that Hoechst 33342 has specific anti-ASFV activity. We expect this novel tool to be useful both in the further study of ASFV replication as in the screening of new specific antiviral compounds.

非洲猪瘟病毒(ASFV)感染导致家猪经常患上致命疾病,自 2021 年以来已波及全球 50 多个国家,对动物福利和经济造成了重大影响。为有效控制该疾病,迫切需要开发有效的疫苗或抗病毒药物。病毒复制的活体检测已被用作筛选和鉴定其他含 dsDNA 基因组病毒的抗病毒化合物的工具。在这里,我们通过构建和鉴定一种新型重组病毒,将 ANCHOR 荧光 DNA 标记系统应用于 ASFV。我们的研究表明,这种病毒具有生命力,能有效标记病毒 DNA 复制位点,并能对其进行实时检测和定量。此外,我们还利用高含量细胞显微镜检测了双苯并咪唑类化合物的抗病毒活性,结果表明 Hoechst 33342 具有特异性抗 ASFV 活性。我们希望这种新工具能在进一步研究 ASFV 复制和筛选新的特异性抗病毒化合物方面发挥作用。
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Antiviral research
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