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Three in one: An effective and universal vaccine expressing heterologous tandem RBD trimer by rabies virus vector protects mice against SARS-CoV-2 三合一:通过狂犬病毒载体表达异源串联 RBD 三聚体的有效通用疫苗可保护小鼠免受 SARS-CoV-2 的感染。
IF 7.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-11 DOI: 10.1016/j.antiviral.2024.105905
Jingbo Huang , Weiqi Wang , Hailun Li , Yujie Bai , Yumeng Song , Cuicui Jiao , Hongli Jin , Pei Huang , Haili Zhang , Xianzhu Xia , Feihu Yan , Yuanyuan Li , Hualei Wang

The rapid emergence of Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2) variants, coupled with severe immune evasion and imprinting, has jeopardized the vaccine efficacy, necessitating urgent development of broad protective vaccines. Here, we propose a strategy employing recombinant rabies viruses (RABV) to create a universal SARS-CoV-2 vaccine expressing heterologous tandem receptor-binding domain (RBD) trimer from the SARS-CoV-2 Prototype, Delta, and Omicron strains (SRV-PDO). The results of mouse immunization indicated that SRV-PDO effectively induced cellular and humoral immune responses, and demonstrated higher immunogenicity and broader SARS-CoV-2 neutralization compared to the recombinant RABVs that only expressed RBD monomers. Moreover, SRV-PDO exhibited full protection against SARS-CoV-2 in the challenge assay. This study demonstrates that recombinant RABV expressing tandem RBD-heterotrimer as a multivalent immunogen could elicit a broad-spectrum immune response and potent protection against SARS-CoV-2, making it a promising candidate for future human or veterinary vaccines and offering a novel perspective in other vaccine design.

严重急性呼吸系统综合征冠状病毒 2 型(SARS-CoV-2)变种的迅速出现,加上严重的免疫逃避和印迹,已危及疫苗的效力,因此迫切需要开发具有广泛保护作用的疫苗。在此,我们提出了一种采用重组狂犬病毒(RABV)的策略,从 SARS-CoV-2 原型、Delta 和 Omicron 株(SRV-PDO)中提取表达异源串联受体结合域(RBD)三聚体的通用 SARS-CoV-2 疫苗。小鼠免疫结果表明,与仅表达 RBD 单体的重组 RABV 相比,SRV-PDO 能有效诱导细胞和体液免疫反应,并表现出更高的免疫原性和更广泛的 SARS-CoV-2 中和作用。此外,SRV-PDO 在挑战试验中表现出对 SARS-CoV-2 的全面保护。这项研究表明,表达串联 RBD-三聚体作为多价免疫原的重组 RABV 可引起广谱免疫反应,并对 SARS-CoV-2 提供强效保护,使其成为未来人类或兽医疫苗的理想候选物,并为其他疫苗设计提供了新的视角。
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引用次数: 0
A new compound, phomaherbarine A, induces cytolytic reactivation in epstein-barr virus-positive B cell lines 一种新化合物--磷脂酰巴比妥碱 A--可诱导 Epstein-Barr 病毒阳性 B 细胞系的细胞溶解再活化。
IF 7.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-10 DOI: 10.1016/j.antiviral.2024.105906
So-Eun Bae , Jin Won Choi , Ji-Woon Hong , Hyeri Ku , Kyu-Young Sim , Gwang-Hoon Ko , Dae Sik Jang , Sang Hee Shim , Sung-Gyoo Park

Epstein-Barr virus (EBV), the first virus found to induce cancer in humans, has been frequently detected in various types of B cell lymphomas. During its latent phase, EBV expresses a limited set of proteins crucial for its persistence. Induction of the lytic phase of EBV has shown promise in the treatment of EBV-associated malignancies. The present study assessed the ability of phomaherbarine A, a novel compound derived from the endophytic fungus Phoma herbarum DBE-M1, to stimulate lytic replication of EBV in B95-8 cells. Phomaherbarine A was found to efficiently initiate the expression of both early and late EBV lytic genes in B95-8 cells, with this initiation being further heightened by the addition of phorbol myristate acetate and sodium butyrate. Moreover, phomaherbarine A demonstrated notable cytotoxicity against the EBV-associated B cell lymphoma cell lines B95-8 and Raji. Mechanistically, phomaherbarine A induces apoptosis in these cells through the activation of caspase-3/7. When combined with ganciclovir, phomaherbarine A does not interfere with the reduction of viral replication by ganciclovir and sustains its apoptosis induction. In conclusion, these findings indicate that phomaherbarine A may be a promising candidate for therapeutic intervention in patients with EBV-associated B cell lymphomas.

爱泼斯坦-巴尔病毒(EBV)是人类发现的第一种诱发癌症的病毒,经常在各种类型的 B 细胞淋巴瘤中被检测到。在潜伏期,EBV 会表达对其存活至关重要的一组有限蛋白质。诱导 EBV 的溶解阶段已显示出治疗 EBV 相关恶性肿瘤的前景。本研究评估了从内生真菌 Phoma herbarum DBE-M1 中提取的新型化合物 Phomaherbarine A 在 B95-8 细胞中刺激 EBV 溶解复制的能力。研究发现,Phomaherbarine A 能有效地启动 B95-8 细胞中早期和晚期 EBV 溶菌基因的表达,加入乙酸薄荷醇肉豆蔻酸酯和丁酸钠后,这种启动作用会进一步增强。此外,磷脂酰巴豆碱 A 对与 EBV 相关的 B 细胞淋巴瘤细胞系 B95-8 和 Raji 具有显著的细胞毒性。从机理上讲,磷马赫巴林 A 可通过激活 caspase-3/7 诱导这些细胞凋亡。当 phomaherbarine A 与更昔洛韦合用时,不会干扰更昔洛韦减少病毒复制的作用,并能维持其诱导细胞凋亡的作用。总之,这些研究结果表明,磷马赫巴林 A 有可能成为治疗 EBV 相关 B 细胞淋巴瘤患者的候选药物。
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引用次数: 0
Lectibodies as antivirals 作为抗病毒药物的抗体。
IF 7.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-10 DOI: 10.1016/j.antiviral.2024.105901
Ian Carlosalberto Santisteban Celis , Nobuyuki Matoba

Growing concerns regarding the emergence of highly transmissible viral diseases highlight the urgent need to expand the repertoire of antiviral therapeutics. For this reason, new strategies for neutralizing and inhibiting these viruses are necessary. A promising approach involves targeting the glycans present on the surfaces of enveloped viruses. Lectins, known for their ability to recognize specific carbohydrate molecules, offer the potential for glycan-targeted antiviral strategies. Indeed, numerous studies have reported the antiviral effects of various lectins of both endogenous and exogenous origins. However, many lectins in their natural forms, are not suitable for use as antiviral therapeutics due to toxicity, other unfavorable pharmacological effects, and/or unreliable manufacturing sources. Therefore, improvements are crucial for employing lectins as effective antiviral therapeutics. A novel approach to enhance lectins’ suitability as pharmaceuticals could be the generation of recombinant lectin-Fc fusion proteins, termed “lectibodies.” In this review, we discuss the scientific rationale behind lectin-based antiviral strategies and explore how lectibodies could facilitate the development of new antiviral therapeutics. We will also share our perspective on the potential of these molecules to transcend their potential use as antiviral agents.

人们对高传播病毒性疾病的出现日益关注,这凸显了扩大抗病毒疗法范围的迫切需要。因此,有必要采用新的策略来中和并抑制这些病毒。一种很有前景的方法是以包膜病毒表面的聚糖为靶标。凝集素以其识别特定碳水化合物分子的能力而闻名,为以聚糖为靶点的抗病毒策略提供了可能性。事实上,许多研究都报道了各种内源性和外源性凝集素的抗病毒作用。然而,由于毒性、其他不利的药理作用和/或不可靠的制造来源,许多天然形式的凝集素并不适合用作抗病毒疗法。因此,要将凝集素用作有效的抗病毒疗法,必须对其进行改进。提高凝集素作为药物的适用性的一种新方法可能是生成重组凝集素-Fc融合蛋白,即 "凝集体"。在这篇综述中,我们将讨论基于凝集素的抗病毒策略背后的科学原理,并探讨凝集体如何促进新型抗病毒疗法的开发。我们还将分享我们对这些分子作为抗病毒药物的潜在用途的看法。
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引用次数: 0
New technologies in therapeutic antibody development: The next frontier for treating infectious diseases 治疗性抗体开发的新技术:治疗传染病的下一个前沿。
IF 7.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-09 DOI: 10.1016/j.antiviral.2024.105902
Sheila M. Keating , Brett W. Higgins

Adaptive immunity to viral infections requires time to neutralize and clear viruses to resolve infection. Fast growing and pathogenic viruses are quickly established, are highly transmissible and cause significant disease burden making it difficult to mount effective responses, thereby prolonging infection. Antibody-based passive immunotherapies can provide initial protection during acute infection, assist in mounting an adaptive immune response, or provide protection for those who are immune suppressed or immune deficient. Historically, plasma-derived antibodies have demonstrated some success in treating diseases caused by viral pathogens; nonetheless, limitations in access to product and antibody titer reduce success of this treatment modality. Monoclonal antibodies (mAbs) have proven an effective alternative, as it is possible to manufacture highly potent and specific mAbs against viral targets on an industrial scale. As a result, innovative technologies to discover, engineer and manufacture specific and potent antibodies have become an essential part of the first line of treatment in pathogenic viral infections. However, a mAb targeting a specific epitope will allow escape variants to outgrow, causing new variant strains to become dominant and resistant to treatment with that mAb. Methods to mitigate escape have included combining mAbs into cocktails, creating bi-specific or antibody drug conjugates but these strategies have also been challenged by the potential development of escape mutations. New technologies in developing antibodies made as recombinant polyclonal drugs can integrate the strength of poly-specific antibody responses to prevent mutational escape, while also incorporating antibody engineering to prevent antibody dependent enhancement and direct adaptive immune responses.

病毒感染的适应性免疫需要时间来中和和清除病毒,以解决感染问题。快速生长的致病性病毒很快就会形成,传播性强,会造成严重的疾病负担,因此很难产生有效的反应,从而延长感染时间。以抗体为基础的被动免疫疗法可在急性感染期间提供初步保护,协助启动适应性免疫反应,或为免疫抑制或免疫缺陷患者提供保护。从历史上看,血浆衍生抗体在治疗病毒病原体引起的疾病方面取得了一定的成功;然而,由于产品获取途径和抗体滴度的限制,这种治疗方式的成功率较低。单克隆抗体(mAbs)已被证明是一种有效的替代方法,因为可以在工业规模上生产针对病毒靶点的高效特异性 mAbs。因此,发现、设计和制造特异性强效抗体的创新技术已成为治疗致病性病毒感染的第一线疗法的重要组成部分。然而,针对特定表位的 mAb 会允许逃逸变异株生长,导致新的变异株成为优势株,并对该 mAb 的治疗产生抗药性。缓解逃逸的方法包括将 mAb 组合成鸡尾酒、创建双特异性或抗体药物共轭物,但这些策略也受到了逃逸变异潜在发展的挑战。以重组多克隆药物形式开发抗体的新技术可以整合多特异性抗体反应的强度,防止突变逃逸,同时还可以结合抗体工程,防止抗体依赖性增强和直接适应性免疫反应。
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引用次数: 0
SRX3177, a CDK4/6-PI3K-BET inhibitor, in combination with an RdRp inhibitor, Molnupiravir, or an entry inhibitor MU-UNMC-2, has potent antiviral activity against the Omicron variant of SARS-CoV-2 SRX3177 是一种 CDK4/6-PI3K-BET 抑制剂,与 RdRp 抑制剂 Molnupiravir 或入口抑制剂 MU-UNMC-2 联合使用,对 SARS-CoV-2 的 Omicron 变体具有很强的抗病毒活性。
IF 7.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-08 DOI: 10.1016/j.antiviral.2024.105904
Kabita Pandey , Arpan Acharya , Dhananjaya Pal , Prashant Jain , Kamal Singh , Donald L. Durden , Tatiana G. Kutateladze , Aniruddha J. Deshpande , Siddappa N. Byrareddy

Despite considerable progress in developing vaccines and antivirals to combat COVID-19, the rapid mutations of the SARS-CoV-2 genome have limited the durability and efficacy of the current vaccines and therapeutic interventions. Hence, it necessitates the development of novel therapeutic approaches or repurposing existing drugs that target either viral life cycle, host factors, or both. Here, we report that SRX3177, a potent triple-activity CDK4/6-PI3K-BET inhibitor, blocks replication of the SARS-CoV-2 Omicron variant with IC50 values at sub-micromolar concentrations without any impact on the cell proliferation of Calu-3 cells at and below its IC50 concentration. When SRX3177 is combined with EIDD-1931 (active moiety of a small-molecule prodrug Molnupiravir) or MU-UNMC-2 (a SARS-CoV-2 entry inhibitor) at a fixed doses matrix, a synergistic effect was observed, leading to the significant reduction in the dose of the individual compounds to achieve similar inhibition of SARS-CoV-2 replication. Herein, we report that the combination of SRX3177/MPV or SRX3177/UM-UNMC-2 has the potential for further development as a combinational therapy against SARS-CoV-2 and in any future outbreak of beta coronavirus.

尽管在开发抗 COVID-19 疫苗和抗病毒药物方面取得了很大进展,但 SARS-CoV-2 基因组的快速变异限制了现有疫苗和治疗干预措施的持久性和有效性。因此,有必要针对病毒生命周期、宿主因素或两者开发新的治疗方法或重新利用现有药物。在这里,我们报告了一种强效的三重活性 CDK4/6-PI3K-BET 抑制剂 SRX3177,它能阻断 SARS-CoV-2 Omicron 变体的复制,其 IC50 值为亚微摩浓度,在其 IC50 浓度及以下不会对 Calu-3 细胞的增殖产生任何影响。当 SRX3177 与 EIDD-1931(小分子原药 Molnupiravir 的活性分子)或 MU-UNMC-2(SARS-CoV-2 进入抑制剂)以固定剂量基质结合使用时,观察到了协同效应,从而显著降低了单个化合物的剂量,以达到类似的抑制 SARS-CoV-2 复制的效果。研究结果表明,SRX3177/MPV 或 SRX3177/UM-UNMC-2 有可能被进一步开发为抗击 SARS-CoV-2 和未来任何β冠状病毒爆发的联合疗法。
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引用次数: 0
Characterization of SARS-CoV-2 replication in human H1299/ACE2 cells: A versatile and practical infection model for antiviral research and beyond SARS-CoV-2 在人类 H1299/ACE2 细胞中复制的特征:一种用于抗病毒研究及其他领域的多功能实用感染模型。
IF 7.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-07 DOI: 10.1016/j.antiviral.2024.105903
Clarisse Salgado-Benvindo , Ali Tas , Jessika C. Zevenhoven-Dobbe , Yvonne van der Meer , Igor A. Sidorov , Anouk A. Leijs , Patrick Wanningen , Anne T. Gelderloos , Puck B. van Kasteren , Eric J. Snijder , Martijn J. van Hemert

A range of cell culture infection models have been used to study SARS-CoV-2 and perform antiviral drug research. Commonly used African green monkey Vero, human lung-derived Calu-3 and ACE2+TMPRSS2-expressing A549 cells, each have their limitations. Here, we describe human ACE2-expressing H1299 lung cells as a more efficient and robust model for SARS-CoV-2 research. These cells are as easy to handle as Vero cells, support SARS-CoV-2 replication to high titers, display a functional innate immune response and are suitable for plaque assays, microscopy, the production of (genetically stable) virus stocks and antiviral assays. H1299/ACE2-based (CPE reduction) assays can be performed without adding a P-gP drug efflux pump inhibitor, which is often required in Vero-based assays. Moreover, H1299/ACE2 cells allowed us to perform CPE reduction assays with omicron variants that did not work in Vero-based assays. In summary, H1299/ACE2 cells are a versatile infection model to study SARS-CoV-2 replication in the context of antiviral drug development and virus-host interaction studies.

在研究 SARS-CoV-2 和进行抗病毒药物研究时,使用了一系列细胞培养感染模型。常用的非洲绿猴 Vero、人肺源 Calu-3 和 ACE2+TMPRSS2 表达的 A549 细胞各有其局限性。在这里,我们描述了表达人 ACE2 的 H1299 肺细胞,它是研究 SARS-CoV-2 的一种更有效、更强大的模型。这些细胞与 Vero 细胞一样易于处理,支持高滴度的 SARS-CoV-2 复制,显示出功能性先天免疫反应,适用于斑块检测、显微镜检查、生产(基因稳定的)病毒储备和抗病毒检测。基于 H1299/ACE2(CPE 减少)的检测可以在不添加 P-gP 药物外排泵抑制剂的情况下进行,而在基于 Vero 的检测中通常需要添加 P-gP 药物外排泵抑制剂。此外,H1299/ACE2 细胞还能让我们用在基于 Vero 的试验中不起作用的欧米克隆变体进行 CPE 还原试验。总之,H1299/ACE2 细胞是在抗病毒药物开发和病毒-宿主相互作用研究中研究 SARS-CoV-2 复制的多功能感染模型。
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引用次数: 0
Double synergic chitosan-coated poly (lactic-co-glycolic) acid nanospheres loaded with nucleic acids as an intranasally administered vaccine delivery system to control the infection of foot-and-mouth disease virus 载入核酸的双协同壳聚糖包覆聚(乳酸-共聚-乙醇)酸纳米球作为一种鼻内给药疫苗递送系统,用于控制口蹄疫病毒感染。
IF 7.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-04 DOI: 10.1016/j.antiviral.2024.105900
Xian Li , Zhong-wang Zhang , Fu-dong Zhang , Jia-hao Li , Jian-liang Lv , Li-Ping Zhang , Kai-ge Zhai , Yong-Lu Wang , Hui-chen Guo , Xin-sheng Liu , Li Pan

Background & aims

The spread of foot-and-mouth disease virus (FMDV) through aerosol droplets among cloven-hoofed ungulates in close contact is a major obstacle for successful animal husbandry. Therefore, the development of suitable mucosal vaccines, especially nasal vaccines, to block the virus at the initial site of infection is crucial.

Patients and methods

Here, we constructed eukaryotic expression plasmids containing the T and B-cell epitopes (pTB) of FMDV in tandem with the molecular mucosal adjuvant Fms-like tyrosine kinase receptor 3 ligand (Flt3 ligand, FL) (pTB-FL). Then, the constructed plasmid was electrostatically attached to mannose-modified chitosan-coated poly(lactic-co-glycolic) acid (PLGA) nanospheres (MCS-PLGA-NPs) to obtain an active nasal vaccine targeting the mannose-receptor on the surface of antigen-presenting cells (APCs).

Results

The MCS-PLGA-NPs loaded with pTB-FL not only induced a local mucosal immune response, but also induced a systemic immune response in mice. More importantly, the nasal vaccine afforded an 80% protection rate against a highly virulent FMDV strain (AF72) when it was subcutaneously injected into the soles of the feet of guinea pigs.

Conclusions

The nasal vaccine prepared in this study can effectively induce a cross-protective immune response against the challenge with FMDV of same serotype in animals and is promising as a potential FMDV vaccine.

背景与目的:口蹄疫病毒(FMDV)通过气溶胶飞沫在密切接触的蹄类动物之间传播是成功饲养动物的一大障碍。因此,开发合适的粘膜疫苗,尤其是鼻腔疫苗,以在最初感染部位阻断病毒至关重要。然后,将构建的质粒静电连接到甘露糖修饰的壳聚糖包覆的聚乳酸-聚乙二醇酸(PLGA)纳米球(MCS-PLGA-NPs)上,从而获得一种靶向抗原递呈细胞(APCs)表面甘露糖受体的活性鼻腔疫苗:结果:负载 pTB-FL 的 MCS-PLGA-NPs 不仅能诱导局部粘膜免疫反应,还能诱导小鼠产生全身免疫反应。更重要的是,将鼻腔疫苗皮下注射到豚鼠的足底,可使其对高致病性口蹄疫病毒株(AF72)产生 80% 的保护率:本研究制备的鼻腔疫苗可有效诱导动物对同一血清型口蹄疫病毒挑战的交叉保护性免疫反应,有望成为一种潜在的口蹄疫病毒疫苗。
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引用次数: 0
Potency of a small molecule that targets the molluscum contagiosum virus processivity factor increases when conjugated to a tripeptide 针对软疣病毒加工因子的小分子与三肽共轭后效力增强
IF 7.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-03 DOI: 10.1016/j.antiviral.2024.105899
Hancheng Guan , Manunya Nuth , Richard W. Scott , Michael H. Parker , Eric D. Strobel , Allen B. Reitz , John L. Kulp III , Robert P. Ricciardi

We recently developed compound FC-7269 for targeting the Molluscum contagiosum virus processivity factor (mD4) and demonstrated its ability to inhibit viral processive DNA synthesis in vitro and cellular infection of an mD4-dependent virus (Antiviral Res 211, 2023,105520). However, despite a thorough medicinal chemistry campaign we were unable to generate a potent second analog as a requisite for drug development. We overcame this impasse, by conjugating a short hydrophobic trivaline peptide to FC-7269 to produce FC-TriVal-7269 which significantly increased antiviral potency and reduced cellular toxicity.

我们最近开发了针对传染性软疣病毒过程因子(mD4)的化合物 FC-7269,并证明了其在体外抑制病毒过程 DNA 合成和抑制依赖 mD4 病毒的细胞感染的能力(Antiviral Res 211, 2023,105520)。然而,尽管我们进行了全面的药物化学研究,但仍无法生成药物开发所需的强效第二类似物。我们克服了这一僵局,在 FC-7269 上连接了一个短的疏水三价肽,生成了 FC-TriVal-7269,显著提高了抗病毒效力并降低了细胞毒性。
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引用次数: 0
Screening and optimization of shark nanobodies against SARS-CoV-2 spike RBD 针对 SARS-CoV-2 Spike RBD 的鲨鱼纳米抗体的筛选和优化。
IF 7.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-29 DOI: 10.1016/j.antiviral.2024.105898
Xiaochun Liu , Yanqing Wang , Lishan Sun , Guokai Xiao , Ning Hou , Jin Chen , Wei Wang , Ximing Xu , Yuchao Gu

SARS-CoV-2 continues to threaten human health, antibody therapy is one way to control the infection. Because new SARS-CoV-2 mutations are constantly emerging, there is an urgent need to develop broadly neutralizing antibodies to block the viral entry into host cells. VNAR from sharks is the smallest natural antigen binding domain, with the advantages of small size, flexible paratopes, good stability, and low manufacturing cost. Here, we used recombinant SARS-CoV-2 Spike-RBD to immunize sharks and constructed a VNAR phage display library. VNAR R1C2, selected from the library, efficiently binds to the RBD domain and blocks the infection of ACE2-positive cells by pseudovirus. Next, homologous bivalent VNARs were constructed through the tandem fusion of two R1C2 units, which enhanced both the affinity and neutralizing activity of R1C2. R1C2 was predicted to bind to a relatively conserved region within the RBD. By introducing mutations at four key binding sites within the CDR3 and HV2 regions of R1C2, the affinity and neutralizing activity of R1C2 were significantly improved. Furthermore, R1C2 also exhibits an effective capacity of binding to the Omicron variants (BA.2 and XBB.1). Together, these results suggest that R1C2 could serve as a valuable candidate for preventing and treating SARS-CoV-2 infections.

SARS-CoV-2 继续威胁人类健康,抗体疗法是控制感染的一种方法。由于 SARS-CoV-2 不断出现新的变异,因此迫切需要开发广谱中和抗体来阻止病毒进入宿主细胞。鲨鱼的 VNAR 是最小的天然抗原结合域,具有体积小、副基团灵活、稳定性好、制造成本低等优点。在这里,我们使用重组 SARS-CoV-2 Spike-RBD 对鲨鱼进行免疫,并构建了一个 VNAR 噬菌体展示文库。从文库中筛选出的 VNAR R1C2 能有效地与 RBD 结构域结合,阻断伪病毒对 ACE2 阳性细胞的感染。接下来,通过串联融合两个 R1C2 单元,构建了同源的二价 VNAR,这增强了 R1C2 的亲和力和中和活性。据预测,R1C2 将与 RBD 中一个相对保守的区域结合。通过在 R1C2 的 CDR3 和 HV2 区域内的四个关键结合位点引入突变,R1C2 的亲和力和中和活性得到了显著提高。此外,R1C2 还能有效地与 Omicron 变体(BA.2 和 XBB.1)结合。这些结果表明,R1C2 可作为预防和治疗 SARS-CoV-2 感染的重要候选药物。
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引用次数: 0
Polyoxometalate exerts broad-spectrum activity against human respiratory viruses hampering viral entry 聚氧化金属盐对人类呼吸道病毒具有广谱活性,可阻碍病毒进入人体
IF 7.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-27 DOI: 10.1016/j.antiviral.2024.105897
Irene Arduino , Rachele Francese , Andrea Civra , Elisa Feyles , Monica Argenziano , Marco Volante , Roberta Cavalli , Ali M. Mougharbel , Ulrich Kortz , Manuela Donalisio , David Lembo

Human respiratory viruses have an enormous impact on national health systems, societies, and economy due to the rapid airborne transmission and epidemic spread of such pathogens, while effective specific antiviral drugs to counteract infections are still lacking. Here, we identified two Keggin-type polyoxometalates (POMs), [TiW11CoO40]8- (TiW11Co) and [Ti2PW10O40]7- (Ti2PW10), endowed with broad-spectrum activity against enveloped and non-enveloped human respiratory viruses, i.e., coronavirus (HCoV-OC43), rhinovirus (HRV-A1), respiratory syncytial virus (RSV-A2), and adenovirus (AdV-5). Ti2PW10 showed highly favorable selectivity indexes against all tested viruses (SIs >700), and its antiviral potential was further investigated against human coronaviruses and rhinoviruses. This POM was found to inhibit replication of multiple HCoV and HRV strains, in different cell systems. Ti2PW10 did not affect virus binding or intracellular viral replication, but selectively inhibited the viral entry. Serial passaging of virus in presence of the POM revealed a high barrier to development of Ti2PW10-resistant variants of HRV-A1 or HCoV-OC43. Moreover, Ti2PW10 was able to inhibit HRV-A1 production in a 3D model of the human nasal epithelium and, importantly, the antiviral treatment did not determine cytotoxicity or tissue damage. A mucoadhesive thermosensitive in situ hydrogel formulation for nasal delivery was also developed for Ti2PW10. Overall, good biocompatibility on cell lines and human nasal epithelia, broad-spectrum activity, and absence of antiviral resistance development reveal the potential of Ti2PW10 as an antiviral candidate for the development of a treatment of acute respiratory viral diseases, warranting further studies to identify the specific target/s of the polyanion and assess its clinical potential.

人类呼吸道病毒通过空气快速传播和流行,对国家卫生系统、社会和经济造成了巨大影响,但目前仍缺乏有效的特异性抗病毒药物来对抗感染。在这里,我们发现了两种凯金型多氧金属盐(POMs),即[TiW11CoO40]8-(TiW11Co)和[Ti2PW10O40]7-(Ti2PW10)、冠状病毒(HCoV-OC43)、鼻病毒(HRV-A1)、呼吸道合胞病毒(RSV-A2)和腺病毒(AdV-5)。Ti2PW10 对所有测试病毒都显示出非常有利的选择性指数(SIs >700),并进一步研究了它对人类冠状病毒和鼻病毒的抗病毒潜力。研究发现,在不同的细胞系统中,这种 POM 可抑制多种 HCoV 和 HRV 株系的复制。Ti2PW10 不会影响病毒的结合或细胞内病毒的复制,但会选择性地抑制病毒的进入。在有 POM 存在的情况下对病毒进行连续传递发现,HRV-A1 或 HCoV-OC43 的 Ti2PW10 抗性变异体的发展障碍很大。此外,Ti2PW10 还能抑制人鼻腔上皮细胞三维模型中 HRV-A1 的产生,重要的是,抗病毒治疗不会造成细胞毒性或组织损伤。此外,还为 Ti2PW10 开发了一种用于鼻腔给药的粘液黏性热敏原位水凝胶配方。总之,Ti2PW10 在细胞系和人类鼻腔上皮细胞上具有良好的生物相容性、广谱活性,而且没有产生抗病毒耐药性,这表明它有潜力作为一种候选抗病毒药物用于治疗急性呼吸道病毒性疾病。
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