Antiviral research最新文献_第6页

Negative regulation of SREBP-1/FAS signaling molecules activates the RIG-1/TBK1-mediated IFN-I pathway to inhibit BVDV replication SREBP-1/FAS信号分子的负调控激活RIG-1/ tbk1介导的IFN-I通路，抑制BVDV复制。

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-01-01 DOI: 10.1016/j.antiviral.2024.106054

Shanshan Liu , An Luo , Taolin Que , Yuxin Liang , Yuxin Song , Tianyi Liu , Jing Li , Nan Li , Zechen Zhang , Yu Liu , Zecai Zhang , Yulong Zhou , Xue Wang , Zhanbo Zhu

For many viruses, controlling the process of infection is largely dependent on the enzymes of the fatty acid synthesis (FAS) pathway. An appealing therapeutic target in antiviral research is fatty acid synthetase (FASN), a crucial enzyme in the FAS pathway. Bovine viral diarrhea, caused by the Bovine viral diarrhea virus (BVDV), is a significant viral infectious disease posing a substantial threat to global animal husbandry. Our study revealed that BVDV infection not only upregulates the expression of FAS-related enzymes in BT cells and the blood, liver, and spleen of mice but also markedly enhances the accumulation of lipid droplets, free fatty acids, and triglycerides. The FAS pathway plays a pivotal role throughout the entire BVDV replication cycle. Additionally, administration of the FASN inhibitor C75 and Acetyl CoA carboxylase-1 (ACC-1) inhibitor TOFA significantly reduced the viral content in both serum and organs of BVDV-infected mice, exhibiting inhibitory effects across diverse viral strains. Intriguingly, We found that RIG-1/TBK1-mediated IFN-I signaling inhibits SREBP-1/FAS and reduces BVDV replication. Conversely, targeting a few essential enzymes of SREBP-1/FAS also activates IFN-I signaling. More importantly, FASN inhibitor led to heightened expression of ISGs in mouse spleens by activating the RIG-1/TBK-1 pathway. These findings highlight that FASN inhibitors inhibit BVDV replication through the activation of the RIG-1/TBK-1 pathway to induce ISGs, and offering a novel therapeutic approach for combating BVDV. Thus, it is crucial to negatively regulate SREBP-1/FAS signaling molecules in order to create novel antiviral drugs that are safe, effective, and broad-spectrum.

对许多病毒来说，控制感染过程在很大程度上依赖于脂肪酸合成（FAS）途径的酶。脂肪酸合成酶（FASN）是抗病毒研究中一个很有吸引力的治疗靶点，它是FAS途径中的一个关键酶。牛病毒性腹泻是由牛病毒性腹泻病毒（BVDV）引起的一种严重的病毒性传染病，对全球畜牧业构成重大威胁。我们的研究表明，BVDV感染不仅上调了小鼠BT细胞和血液、肝脏、脾脏中fas相关酶的表达，而且显著增加了脂滴、游离脂肪酸和甘油三酯的积累。FAS途径在整个BVDV复制周期中起着关键作用。此外，给予FASN抑制剂C75和乙酰辅酶a羧化酶-1 （ACC-1）抑制剂TOFA可显著降低bvdv感染小鼠血清和器官中的病毒含量，对不同病毒株均有抑制作用。有趣的是，我们发现RIG-1/ tbk1介导的IFN-I信号传导抑制SREBP-1/FAS并减少BVDV复制。相反，靶向SREBP-1/FAS的一些必需酶也能激活IFN-I信号。更重要的是，FASN抑制剂通过激活RIG-1/TBK-1通路，导致小鼠脾脏中ISGs的表达升高。这些研究结果强调，FASN抑制剂通过激活RIG-1/TBK-1通路来抑制BVDV的复制，从而诱导ISGs，并为对抗BVDV提供了一种新的治疗方法。因此，对SREBP-1/FAS信号分子进行负调控，以创造安全、有效、广谱的新型抗病毒药物至关重要。

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引用次数: 0

N-arylpyrimidinamine (NAPA) compounds are broadly acting inhibitors of human cytomegalovirus infection and spread n -芳基嘧啶胺（NAPA）化合物是广泛作用的人巨细胞病毒感染和传播抑制剂。

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-01-01 DOI: 10.1016/j.antiviral.2024.106044

Kristina E. Atanasoff , Sabrina I. Ophir , Andrea J. Parsons , Jailene Paredes Casado , Nell S. Lurain , Terry L. Bowlin , Timothy J. Opperman , Domenico Tortorella

Human cytomegalovirus (HCMV) is a β-herpesvirus that contributes to the disease burden of immunocompromised and immunomodulated individuals, including transplant recipients and newborns. The FDA-approved HCMV drugs can exhibit drug resistance and severe side effects including bone marrow toxicity, gastrointestinal disruption, and nephrotoxicity. In a previous study, we identified the N-arylpyrimidinamine (NAPA) compound series as a new class of HCMV inhibitors that target early stages of infection. Here we describe the inhibitory activity of two potent NAPA analogs, MBXC-4336 and MBX-4992, that broadly block infection and spread. MBXC-4336 and MBX-4992 effectively inhibited infection by diverse HCMV strains and significantly prevented virus spread in fibroblast and epithelial cells as evaluated by quantifying infected cells and viral genome levels. Further, the NAPA compounds limited replication of clinical HCMV isolates, including a ganciclovir-resistant strain. Importantly, combination studies of NAPA compounds with ganciclovir demonstrated additive or synergistic inhibition of HCMV spread. Collectively, NAPA compounds have therapeutic potential for development as a novel class of anti-HCMV drugs.

人巨细胞病毒（HCMV）是一种β-疱疹病毒，可导致免疫功能低下和免疫调节个体（包括移植受体和新生儿）的疾病负担。fda批准的HCMV药物可表现出耐药性和严重的副作用，包括骨髓毒性、胃肠道紊乱和肾毒性。在之前的研究中，我们发现n -芳基嘧啶胺（NAPA）化合物系列是一类针对早期感染的HCMV抑制剂。在这里，我们描述了两种有效的NAPA类似物MBXC-4336和MBX-4992的抑制活性，它们广泛阻断感染和传播。MBXC-4336和MBX-4992可有效抑制多种HCMV毒株的感染，并通过对感染细胞和病毒基因组水平的量化评估，显著阻止病毒在成纤维细胞和上皮细胞中的传播。此外，NAPA化合物限制了临床HCMV分离株的复制，包括抗更昔洛韦菌株。重要的是，NAPA化合物与更昔洛韦的联合研究证明了对HCMV传播的加性或协同抑制。总的来说，NAPA化合物作为一类新型抗hcmv药物具有开发的治疗潜力。

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引用次数: 0

Construction of a recombinant African swine fever virus with firefly luciferase and eGFP reporter genes and its application in high-throughput antiviral drug screening 构建带有萤火虫荧光素酶和 eGFP 报告基因的重组非洲猪瘟病毒及其在高通量抗病毒药物筛选中的应用。

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-01-01 DOI: 10.1016/j.antiviral.2024.106058

Xinglin He , Pengfei Li , Hua Cao , Xiaoling Zhang , Mengjia Zhang , Xuexiang Yu , Yumei Sun , Ahmed H. Ghonaim , Hailong Ma , Yongtao Li , Kaizhi Shi , Hongmei Zhu , Qigai He , Wentao Li

African Swine Fever (ASF) is a highly lethal and contagious disease in pigs caused by African Swine Fever Virus (ASFV), which primarily infects domestic pigs and wild boars, with a mortality rate of up to 100%. Currently, there are no commercially available vaccines or drugs that are both safe and effective against ASFV. The ASFV 0428C strain was continuously passaged in Vero cells, and the adapted ASFV demonstrated efficient replication in Vero cells. The adapted ASFV was used as the parental virus, and an expression cassette encoding a dual reporter gene for firefly luciferase (Fluc) and enhanced green fluorescent protein (eGFP) was inserted into the ASFV genome using CRISPR/Cas9 gene editing technology to construct a recombinant ASFV variant (rASFV-FLuc-eGFP). rASFV-Fluc-eGFP was genetically stable, effectively infected porcine alveolar macrophages (PAM) and Vero cells, and expressed Fluc and eGFP concurrently. This study provides a tool for investigating the infection and pathogenic mechanisms of ASFV, as well as for screening essential host genes and antiviral drugs. Additionally, a high-throughput screening model of antiviral drugs was established based on rASFV-FLuc-eGFP in passaged cells, 218 compounds from the FDA-approved compound library were screened, and 5 candidate compounds with significant inhibitory effects in Vero cells were identified. The inhibitory effects on ASFV were further validated in both Vero and PAM cells, resulting in the identification of Salvianolic acid C (SAC), which demonstrated inhibitory effects and safety in both cell types. SAC is a candidate drug for the prevention and control of ASFV and shows promising application prospects.

非洲猪瘟（ASF）是一种由非洲猪瘟病毒（ASFV）引起的猪高致死率和传染性疾病，主要感染家猪和野猪，死亡率高达100%。目前，市面上还没有既安全又有效的抗非洲猪瘟疫苗或药物。ASFV 0428C在Vero细胞中连续传代，适应的ASFV在Vero细胞中表现出高效的复制。采用改编后的ASFV作为亲本病毒，利用CRISPR/Cas9基因编辑技术将编码萤火虫荧光素酶（Fluc）和增强型绿色荧光蛋白（eGFP）双报告基因的表达盒插入ASFV基因组，构建重组ASFV变体（rasfv - fuc -eGFP）。rASFV-Fluc-eGFP基因稳定，能有效感染猪肺泡巨噬细胞（PAM）和Vero细胞，并同时表达Fluc和eGFP。本研究为探究ASFV的感染和致病机制、筛选必需宿主基因和抗病毒药物提供了工具。此外，基于rasfv - fc - egfp在传代细胞中建立抗病毒药物的高通量筛选模型，从fda批准的化合物文库中筛选218个化合物，鉴定出5个对Vero细胞具有显著抑制作用的候选化合物。在Vero细胞和PAM细胞中进一步验证了对ASFV的抑制作用，鉴定出Salvianolic acid C (SAC)，在两种细胞类型中均显示出抑制作用和安全性。SAC是预防和控制非洲猪瘟的候选药物，具有良好的应用前景。

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引用次数: 0

Molecular analysis of the 2022 mpox outbreak and antiviral activity of dihydroorotate dehydrogenase inhibitors against orthopoxviruses 2022年麻疹暴发的分子分析及二氢酸脱氢酶抑制剂对正痘病毒的抗病毒活性。

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-01-01 DOI: 10.1016/j.antiviral.2024.106043

Arne Cordsmeier , Alexandra Herrmann , Christian Gege , Hella Kohlhof , Klaus Korn , Armin Ensser

Monkeypox virus (MPXV) has caused a large pandemic outbreak in 2022 with more than 90.000 confirmed cases and 181 deaths. Notably, signs of microevolution and host adaption have been observed. Here, we demonstrate that viral genomes from Franconia, Bavaria acquired different mutations. Three isolates obtained from diagnostic samples, submitted from suspected Mpox cases, show differences in their replication capacities. One MPXV isolate which shows the fastest replication kinetics and higher viral loads, possesses a unique non-synonymous mutation (D616L) in the A11L protein (gene OPG136), which encodes for a protein that is part of a major viral core structure. In regard to pandemic preparedness and future outbreaks, we analyzed the antiviral activity of dihydroorotate dehydrogenase (DHODH) inhibitors, and show that they are active against MPXV, vaccinia virus (VACV), and cowpox virus (CPXV) and therefore likely against orthopoxviruses in general. In agreement with that, we also demonstrated that chemical optimization leads to compounds with EC₅₀ values in the sub-nanomolar range, associated with low cytotoxicity, which forms a good basis for future drug development from this chemical series.

猴痘病毒（MPXV）在2022年造成了大流行疫情，有9万多例确诊病例和181例死亡。值得注意的是，已经观察到微进化和宿主适应的迹象。在这里，我们证明了来自巴伐利亚州Franconia的病毒基因组获得了不同的突变。从疑似m痘病例提交的诊断样本中获得的三株分离株显示出其复制能力的差异。一种MPXV分离物显示出最快的复制动力学和更高的病毒载量，在A11L蛋白（基因OPG136）中具有独特的非同义突变（D616L），该突变编码一种主要病毒核心结构的蛋白质。关于大流行的准备和未来的爆发，我们分析了二氢羟酸脱氢酶（DHODH）抑制剂的抗病毒活性，并表明它们对MPXV、痘苗病毒（VACV）和牛痘病毒（CPXV）有活性，因此可能对一般的正痘病毒有活性。与此一致，我们还证明了化学优化导致化合物的EC50值在亚纳摩尔范围内，与低细胞毒性相关，这为该化学系列的未来药物开发奠定了良好的基础。

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引用次数: 0

Inhibitors of dihydroorotate dehydrogenase synergize with the broad antiviral activity of 4′-fluorouridine 二氢乙酸脱氢酶抑制剂与4′-氟吡啶的广泛抗病毒活性协同作用。

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-01-01 DOI: 10.1016/j.antiviral.2024.106046

Leon Schrell , Hannah L. Fuchs , Antje Dickmanns , David Scheibner , Judith Olejnik , Adam J. Hume , Wencke Reineking , Theresa Störk , Martin Müller , Annika Graaf-Rau , Sandra Diederich , Stefan Finke , Wolfgang Baumgärtner , Elke Mühlberger , Anne Balkema-Buschmann , Matthias Dobbelstein

RNA viruses present a constant threat to human health, often with limited options for vaccination or therapy. Notable examples include influenza viruses and coronaviruses, which have pandemic potential. Filo- and henipaviruses cause more limited outbreaks, but with high case fatality rates. All RNA viruses rely on the activity of a virus-encoded RNA-dependent RNA polymerase (RdRp). An antiviral nucleoside analogue, 4′-Fluorouridine (4′-FlU), targets RdRp and diminishes the replication of several RNA viruses, including influenza A virus and SARS-CoV-2, through incorporation into nascent viral RNA and delayed chain termination. However, the effective concentration of 4′-FlU varied among different viruses, raising the need to fortify its efficacy. Here we show that inhibitors of dihydroorotate dehydrogenase (DHODH), an enzyme essential for pyrimidine biosynthesis, can synergistically enhance the antiviral effect of 4′-FlU against influenza A viruses, SARS-CoV-2, henipaviruses, and Ebola virus. Even 4′-FlU-resistant mutant influenza A virus was re-sensitized towards 4′-FlU by DHODH inhibition. The addition of uridine rescued influenza A virus replication, strongly suggesting uridine depletion as a mechanism of this synergy. 4′-FlU was also highly effective against SARS-CoV-2 in a hamster model of COVID. We propose that the impairment of endogenous uridine synthesis by DHODH inhibition enhances the incorporation of 4′-FlU into viral RNAs. This strategy may be broadly applicable to enhance the efficacy of pyrimidine nucleoside analogues for antiviral therapy.

RNA病毒对人类健康构成持续威胁，通常只有有限的疫苗接种或治疗选择。值得注意的例子包括具有大流行潜力的流感病毒和冠状病毒。丝状病毒和亨尼帕病毒引起的暴发更有限，但致死率很高。所有RNA病毒都依赖于病毒编码的RNA依赖性RNA聚合酶（RdRp）的活性。一种抗病毒核苷类似物4′-氟吡啶（4′-FlU）靶向RdRp，并通过与新生病毒RNA结合和延迟链终止来减少几种RNA病毒的复制，包括甲型流感病毒和SARS-CoV-2。然而，4'-FlU的有效浓度在不同的病毒中有所不同，因此需要加强其功效。本研究表明，二氢乙酸脱氢酶（DHODH）是嘧啶生物合成所必需的酶，其抑制剂可以协同增强4'-FlU对甲型流感病毒、SARS-CoV-2、亨尼帕病毒和埃博拉病毒的抗病毒作用。即使是抗4'-FlU突变型甲型流感病毒也能通过DHODH抑制对4'-FlU重新致敏。尿嘧啶的加入挽救了甲型流感病毒的复制，这强烈表明尿嘧啶耗竭是这种协同作用的一种机制。在新冠病毒仓鼠模型中，4′-FlU对SARS-CoV-2也非常有效。我们认为，抑制DHODH对内源性尿苷合成的损害促进了4'-FlU与病毒rna的结合。该策略可广泛应用于提高嘧啶核苷类似物抗病毒治疗的疗效。

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引用次数: 0

Crimean-Congo hemorrhagic fever virus replicon particle vaccine is safe and elicits functional, non-neutralizing anti-nucleoprotein antibodies and T cell activation in rhesus macaques 克里米亚-刚果出血热病毒复制子颗粒疫苗是安全的，并在恒河猴中引起功能性、非中和性抗核蛋白抗体和T细胞活化。

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-01-01 DOI: 10.1016/j.antiviral.2024.106045

Alyssa Kleymann , Elif Karaaslan , Florine E.M. Scholte , Teresa E. Sorvillo , Stephen R. Welch , Éric Bergeron , Stephanie Elser , Melvyn R. Almanzar-Jordan , Eric Velazquez , Sarah C. Genzer , Sherrie M. Jean , Christina F. Spiropoulou , Jessica R. Spengler

Advancement of vaccine candidates that demonstrate protective efficacy in screening studies necessitates detailed safety and immunogenicity investigations in pre-clinical models. A non-spreading Crimean-Congo hemorrhagic fever virus (CCHFV) viral replicon particle (VRP) vaccine was developed for single-dose administration to protect against disease. To date, several studies have supported safety, immunogenicity, and efficacy of the CCHF VRP in multiple highly sensitive murine models of lethal disease, but the VRP had yet to be evaluated in large animals. Here, we performed studies in non-human primates to further evaluate clinical utility of the VRP vaccine. Twelve adult male and female rhesus macaques were vaccinated intramuscularly and clinical monitoring was performed daily for 28 days. At 3, 7, 14, 21, and 28 days post vaccination, animals were sedated for more detailed clinical assessment; for quantification of vaccine presence in blood and mucosal samples; and for evaluation of hematology, plasma inflammatory markers, and immunogenicity. Consistent with findings in mice, vaccination was well tolerated, with no clinical alterations nor indication of vaccine spread or shedding. In addition, vaccination induced both humoral and cell-mediated responses, with immune profile and kinetics also corroborating data from small animal models. These studies provide key data in non-human primates further supporting development of the VRP for human clinical use.

在筛选研究中显示出保护功效的候选疫苗的进展需要在临床前模型中进行详细的安全性和免疫原性研究。研制了一种非传播性克里米亚-刚果出血热病毒复制子颗粒（VRP）疫苗，用于单剂量给药以预防疾病。迄今为止，已有几项研究支持CCHF VRP在多种高度敏感的致死性疾病小鼠模型中的安全性、免疫原性和有效性，但VRP尚未在大型动物中进行评估。在这里，我们在非人类灵长类动物中进行了研究，以进一步评估VRP疫苗的临床应用。对12只成年雄性和雌性恒河猴进行肌肉注射疫苗接种，并每天进行临床监测。在接种疫苗后3、7、14、21和28天，对动物进行镇静，以进行更详细的临床评估；用于定量血液和粘膜样品中疫苗的存在；用于血液学、血浆炎症标志物和免疫力的评估。与小鼠研究结果一致，疫苗接种耐受性良好，没有临床改变，也没有疫苗传播或脱落的迹象。此外，疫苗接种诱导了体液和细胞介导的反应，免疫谱和动力学也证实了小动物模型的数据。这些研究提供了非人类灵长类动物的关键数据，进一步支持VRP用于人类临床应用的开发。

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引用次数: 0

Edible bird's nest: N- and O-glycan analysis and synergistic anti-avian influenza virus activity with neuraminidase inhibitors 食用燕窝：N-和 O-糖分析以及与神经氨酸酶抑制剂的协同抗禽流感病毒活性。

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2024-12-01 DOI: 10.1016/j.antiviral.2024.106040

Nongluk Sriwilaijaroen , Hisatoshi Hanamatsu , Ikuko Yokota , Takashi Nishikaze , Tetsuo Ijichi , Tadanobu Takahashi , Yoshihiro Sakoda , Jun-ichi Furukawa , Yasuo Suzuki

Zoonotic avian influenza viruses have continued to infect people on occasion. During treatment, antiviral resistant viruses have occasionally emerged, highlighting the need for a novel strategy for treating human illness. After pancreatin treatment, edible bird's nest (EBN), swiftlet saliva consumed for health purposes, possesses anti-avian viral activity by inhibiting receptor-binding hemagglutinin (HA) activity. Glycan analysis revealed an abundance of α2,3Neu5Ac decoy receptors in pancreatin-treated EBN. Fucosylated tri-α2,3Neu5Ac tri-antennary N-glycans (N-35) and di-α2,3Neu5Ac core 2 O-glycans (O-15) are predominant, accounting for 53.46% and 44.66% of total N- and O-glycan amounts, respectively. Isobologram analysis revealed that the treated EBN had a strong synergistic effect with either oseltamivir carboxylate or zanamivir, a competitive inhibitor of receptor-destroying neuraminidases (NAs), against the avian H5N1 virus. Taken together, EBN has the potential to be developed as a food-derived avian viral trap to prevent and decrease avian virus infection as well as in combination with a viral releasing-NA inhibitor to increase therapeutic potency, reduce toxicity, delay resistance development, and potentially prevent pandemic onset.

人畜共患的禽流感病毒仍不时感染人类。在治疗过程中，偶尔会出现对抗病毒药物产生抗药性的病毒，这凸显了治疗人类疾病的新策略的必要性。食用燕窝（EBN）是金丝燕的唾液，具有抗禽流感病毒活性，能抑制受体结合血凝素（HA）的活性。聚糖分析表明，EBN 中含有大量 α2,3Neu5Ac诱饵受体。其中主要是岩藻糖基化的三-α2,3Neu5Ac三触角N-聚糖（N-35）和二-α2,3Neu5Ac核心2 O-聚糖（O-15），分别占N-聚糖总量的53.46%和O-聚糖总量的44.66%。等全息图分析表明，EBN 与奥司他韦羧酸盐或扎那米韦（受体破坏神经氨酸酶（NAs）的竞争性抑制剂）对禽 H5N1 病毒有很强的协同作用。综上所述，EBN 有可能被开发为一种源自食物的禽类病毒捕获剂，用于预防和减少禽类病毒感染，并与病毒释放-NA 抑制剂结合使用，以提高疗效、降低毒性、延缓抗药性的产生，并有可能防止大流行的发生。

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引用次数: 0

Preventing human influenza and coronaviral mono or coinfection by blocking virus-induced sialylation 通过阻断病毒诱导的 Sialylation 来预防人类流感和冠状病毒的单一或混合感染。

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2024-12-01 DOI: 10.1016/j.antiviral.2024.106041

Md Ruhul Amin , Khandaker N. Anwar , M.J. Ashraf , Mahmood Ghassemi , Richard M. Novak

Influenza A viruses (IAVs) and endemic coronaviruses (eCoVs) are common etiologic agents for seasonal respiratory infections. The human H1N1 of IAV and coronavirus OC43 (HCoV-OC43) can result in hospitalization, acute respiratory distress syndrome (ARDS), and even death, particularly in immunocompromised individuals. They infect the epithelium of the respiratory tract by interacting with host cell sialic acid (Sia)- linked receptors whose synthesis is catalyzed by sialyltransferases (STs). Viral coinfection is challenging to treat because of the need to target specific components of two or more distinct pathogens. Emerging drug and vaccine resistance due to the high mutation rate of viral genomes further complicates the treatment and prevention of viral infection. Sialylation mediated by STs may be a potential drug target for treating viral diseases. ST is an attractive target because it could be effective before identifying the pathogen that has occurred, providing a novel direction for overcoming drug resistance and achieving a broad-spectrum antiviral effect. We developed an H1N1 and OC43 mono or coinfection model using 14 days post-plating (14 PP) human primary small airway epithelial cells (HSAEC) grown on transwell inserts at an air-fluid interface (ALI), mimicking in vivo cellular dynamics. Using this model, we have observed that mono or coinfection with OC43 and H1N1 results in increased sialic acid levels and synergistic viral infection. We showed for the first time that H1N1 and OC43 mono- and coinfection in HSAEC caused increased expression and activity of STs, which can be blocked by pan-STs inhibitor (3Fax-Peracetyl Neu5Ac) with no host cell toxicity.

甲型流感病毒（IAV）和地方性冠状病毒（eCoV）是季节性呼吸道感染的常见病原。人感染甲型流感病毒 H1N1 和冠状病毒 OC43（HCoV-OC43）可导致住院、急性呼吸窘迫综合征（ARDS）甚至死亡，尤其是在免疫力低下的人群中。这些病毒通过与宿主细胞的唾液酸（Sia）连接受体相互作用而感染呼吸道上皮细胞，唾液酸受体的合成是由唾液酸转移酶（STs）催化的。病毒合并感染的治疗具有挑战性，因为需要针对两种或两种以上不同病原体的特定成分进行治疗。由于病毒基因组的高突变率，新出现的耐药性和疫苗耐药性使病毒感染的治疗和预防更加复杂。由 STs 介导的糖基化可能是治疗病毒性疾病的潜在药物靶点。ST 是一个很有吸引力的靶点，因为它可以在确定发生的病原体之前就发挥作用，为克服耐药性和实现广谱抗病毒效果提供了一个新的方向。我们开发了一种 H1N1 和 OC43 单感染或混合感染模型，该模型使用人原代小气道上皮细胞（HSAEC），在气-液界面（ALI）的透孔插入物上生长 14 天后（14PP），模拟体内细胞动态。利用这一模型，我们观察到单感染或同时感染 OC43 和 H1N1 会导致硅酸水平升高和病毒协同感染。我们首次发现，H1N1 和 OC43 在 HSAEC 中的单感染和联合感染会导致 STs 的表达和活性增加，而泛 STs 抑制剂（3Fax-Peracetyl Neu5Ac）可阻断 STs 的表达和活性，且不会对宿主细胞产生毒性。

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引用次数: 0

Development of lipopeptide-based HIV-1/2 fusion inhibitors targeting the gp41 pocket site with a new design strategy 用新的设计策略开发基于脂肽的 HIV-1/2 融合抑制剂，靶向 gp41 口袋位点。

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2024-12-01 DOI: 10.1016/j.antiviral.2024.106042

Xiuzhu Geng , Yuanmei Zhu , Yue Gao , Huihui Chong , Yuxian He

Emerging studies demonstrate that lipid conjugation is a vital strategy for designing peptide-based viral fusion inhibitors, and the so-called lipopeptides exhibit greatly improved antiviral activity. In the design of lipopeptides, a flexible linker between the peptide sequence and lipid molecule is generally required, mostly with a short polyethylene glycol or glycine-serine sequence. Very recently, we discovered that the helix-facilitating amino acid sequence “EAAAK” as a rigid linker is a more efficient method in the design of SARS-CoV-2 fusion inhibitory lipopeptides. In this study, we comprehensively characterized the functionalities of different linkers in HIV fusion inhibitors. A short-peptide inhibitor 2P23, which mainly targets the gp41 pocket site, was used as a design template, generating a group of cholesterol-modified lipopeptides. In the inhibition of HIV-1 infection, the lipopeptide inhibitors with a rigid linker were much superior than those with the flexible linkers, as indicated by LP-37 with the “EAAAK” linker and LP-39 with the repeated “EP” amino acid sequences. Both lipopeptides were very potent inhibitors of HIV-2 and simian immunodeficiency (SIV) either. Promisingly, LP-37 displayed high α-helicity, thermostability and binding ability to a target-mimic peptide, and it was metabolically stable when treated with temperature, proteolytic enzymes or human sera. Taken together, our studies have verified a universal strategy for designing viral fusion inhibitors and offered a novel HIV fusion inhibitor for drug development.

新近的研究表明，脂质连接是设计基于多肽的病毒融合抑制剂的重要策略，所谓的脂肽可大大提高抗病毒活性。在设计脂肽时，肽序列和脂质分子之间通常需要一个灵活的连接物，大多是短聚乙二醇或甘氨酸-丝氨酸序列。最近，我们发现以螺旋促进氨基酸序列 "EAAAK "作为刚性连接体是设计 SARS-CoV-2 融合抑制脂肽的一种更有效的方法。在这项研究中，我们全面描述了不同连接体在 HIV 融合抑制剂中的功能特性。以主要针对gp41口袋位点的短肽抑制剂2P23为设计模板，产生了一组胆固醇修饰的脂肽。在抑制 HIV-1 感染方面，刚性连接体的脂肽抑制剂远优于柔性连接体的抑制剂，如带有 "EAAAK "连接体的 LP-37 和带有重复 "EP "氨基酸序列的 LP-39。这两种脂肽对 HIV-2 和猿免疫缺陷病毒（SIV）都有很强的抑制作用。令人欣喜的是，LP-37 显示出很高的α-异构性、热稳定性和与目标模拟肽的结合能力，并且在温度、蛋白水解酶或人类血清的作用下具有代谢稳定性。总之，我们的研究验证了设计病毒融合抑制剂的通用策略，并为药物开发提供了一种新型 HIV 融合抑制剂。

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引用次数: 0

Biological characterization of AB-343, a novel and potent SARS-CoV-2 Mpro inhibitor with pan-coronavirus activity 具有泛冠状病毒活性的新型强效 SARS-CoV-2 Mpro 抑制剂 AB-343 的生物学特性。

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2024-11-20 DOI: 10.1016/j.antiviral.2024.106038

Kayleigh R. McGovern-Gooch , Nagraj Mani , Dimitar Gotchev , Andrzej Ardzinski , Rose Kowalski , Muhammad Sheraz , Holly M. Micolochick Steuer , Breanna Tercero , Xiaohe Wang , Adam Wasserman , Chia-yi Chen , Konstanze von König , Klaus Maskos , Archna Prasad , Michael Blaesse , Andreas Bergmann , Debora L. Konz Makino , Kristi Y. Fan , Steven G. Kultgen , Aaron Lindstrom , Michael J. Sofia

Since the SARS-CoV-2 outbreak, there have been ongoing efforts to identify antiviral molecules with broad coronavirus activity to combat COVID-19. SARS-CoV-2's main protease (M^pro) is responsible for processing the viral polypeptide into non-structural proteins essential for replication. Here, we present the biological characterization of AB-343, a covalent small-molecule inhibitor of SARS-CoV-2 M^pro with potent activity in both cell-based (EC₅₀ = 0.018 μM) and enzymatic (K_i = 0.0028 μM) assays. AB-343 also demonstrated excellent inhibition of M^pro of other human coronaviruses, including those from the alpha (229E and NL63) and beta (SARS-CoV, MERS, OC43, and HKU1) families, suggesting the compound could be active against future coronaviruses. No change in AB-343 potency was observed against M^pro of SARS-CoV-2 variants of concern, including Omicron, suggesting that AB-343 could be developed as a treatment against currently circulating coronaviruses. AB-343 also remained active against several M^pro variants which confer significant resistance to nirmatrelvir and ensitrelvir, which are presently the only M^pro inhibitors authorized for the treatment of COVID-19, further supporting the evaluation of AB-343 as a novel and potent therapeutic for COVID-19 and other coronaviruses.

自 SARS-CoV-2 爆发以来，人们一直在努力寻找具有广泛冠状病毒活性的抗病毒分子来对抗 COVID-19。SARS-CoV-2 的主要蛋白酶（Mpro）负责将病毒多肽加工成复制所必需的非结构蛋白。AB-343 是一种 SARS-CoV-2 Mpro 的共价小分子抑制剂，在基于细胞（EC50 = 0.018 μM）和酶（Ki = 0.0028 μM）的检测中都具有很强的活性。AB-343 还对其他人类冠状病毒的 Mpro 有极佳的抑制作用，包括来自 alpha（229E 和 NL63）和 beta（SARS-CoV、MERS、OC43 和 HKU1）家族的冠状病毒，这表明该化合物对未来的冠状病毒也有活性。针对包括 Omicron 在内的 SARS-CoV-2 变异株的 Mpro，AB-343 的效力没有变化，这表明 AB-343 可开发为针对目前流行的冠状病毒的治疗药物。AB-343还对几种Mpro变体保持活性，这些变体对目前唯一获准用于治疗COVID-19的Mpro抑制剂nirmatrelvir和ensitrelvir具有显著抗药性，这进一步支持了将AB-343作为治疗COVID-19和其他冠状病毒的新型强效疗法的评估。

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引用次数: 0