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Development of nanoparticle vaccines utilizing designed Fc-binding homo-oligomers and RBD-Fc of SARS-CoV-2 利用设计的 SARS-CoV-2 Fc 结合同源异构体和 RBD-Fc 开发纳米颗粒疫苗。
IF 7.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-05-21 DOI: 10.1016/j.antiviral.2024.105917
Yucai Liang , Weiling Xiao , Yuan Peng , Shengshuo Zhang , Jinhua Dong , Jun Zhao , Yuhui Wang , Mengtao Zhang , Zhijun Liu , Bowen Yu

The Fc-fused receptor binding domain (RBD-Fc) vaccine for SARS-CoV-2 has garnered significant attention for its capacity to provide effective and specific immune protection. However, its immunogenicity is limited, highlighting the need for improvement in clinical application. Nanoparticle delivery has been shown to be an effective method for enhancing antigen immunogenicity. In this study, we developed bivalent nanoparticle recombinant protein vaccines by assembling the RBD-Fc of SARS-CoV-2 and Fc-binding homo-oligomers o42.1 and i52.3 into octahedral and icosahedral nanoparticles. The formation of RBD-Fc nanoparticles was confirmed through structural characterization and cell binding experiments. Compared to RBD-Fc dimers, the nanoparticle vaccines induced more potent neutralizing antibodies (nAb) and stronger cellular immune responses. Therefore, using bivalent nanoparticle vaccines based on RBD-Fc presents a promising vaccination strategy against SARS-CoV-2 and offers a universal approach for enhancing the immunogenicity of Fc fusion protein vaccines.

针对 SARS-CoV-2 的 Fc 融合受体结合域(RBD-Fc)疫苗因其提供有效和特异性免疫保护的能力而备受关注。然而,其免疫原性有限,在临床应用中亟待改进。纳米颗粒递送已被证明是提高抗原免疫原性的有效方法。在这项研究中,我们将 SARS-CoV-2 的 RBD-Fc 和 Fc 结合同源异构体 o42.1 和 i52.3 组装成八面体和二十面体纳米颗粒,开发了双价纳米颗粒重组蛋白疫苗。RBD-Fc 纳米粒子的形成通过结构表征和细胞结合实验得到了证实。与 RBD-Fc 二聚体相比,纳米颗粒疫苗能诱导更强的中和抗体(nAb)和更强的细胞免疫反应。因此,使用基于 RBD-Fc 的二价纳米颗粒疫苗是一种很有前景的 SARS-CoV-2 疫苗接种策略,并为增强 Fc 融合蛋白疫苗的免疫原性提供了一种通用方法。
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引用次数: 0
Structural biology of flavivirus NS1 protein and its antibody complexes 黄热病病毒 NS1 蛋白及其抗体复合物的结构生物学。
IF 7.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-05-20 DOI: 10.1016/j.antiviral.2024.105915
Bing Liang Alvin Chew , Qi Pan , Hongli Hu , Dahai Luo

The genus of flavivirus includes many mosquito-borne human pathogens, such as Zika (ZIKV) and the four serotypes of dengue (DENV1-4) viruses, that affect billions of people as evidenced by epidemics and endemicity in many countries and regions in the world. Among the 10 viral proteins encoded by the viral genome, the nonstructural protein 1 (NS1) is the only secreted protein and has been used as a diagnostic biomarker. NS1 has also been an attractive target for its biotherapeutic potential as a vaccine antigen. This review focuses on the recent advances in the structural landscape of the secreted NS1 (sNS1) and its complex with monoclonal antibodies (mAbs). NS1 forms an obligatory dimer, and upon secretion, it has been reported to be hexametric (trimeric dimers) that could dissociate and bind to the epithelial cell membrane. However, high-resolution structural information has been missing about the high-order oligomeric states of sNS1. Several cryoEM studies have since shown that DENV and ZIKV recombinant sNS1 (rsNS1) are in dynamic equilibrium of dimer-tetramer-hexamer states, with tetramer being the predominant form. It was recently revealed that infection-derived sNS1 (isNS1) forms a complex of the NS1 dimer partially embedded in a High-Density Lipoprotein (HDL) particle. Structures of NS1 in complexes with mAbs have also been reported which shed light on their protective roles during infection. The biological significance of the diversity of NS1 oligomeric states remains to be further studied, to inform future research on flaviviral pathogenesis and the development of therapeutics and vaccines. Given the polymorphism of flavivirus NS1 across sample types with variations in antigenicity, we propose a nomenclature to accurately define NS1 based on the localization and origin.

黄病毒属包括许多由蚊子传播的人类病原体,如寨卡(ZIKV)和登革热病毒的四个血清型(DENV1-4),它们影响着数十亿人,在世界许多国家和地区的流行和地方病流行就是证明。在病毒基因组编码的 10 种病毒蛋白中,非结构蛋白 1(NS1)是唯一的分泌蛋白,已被用作诊断生物标志物。NS1 作为疫苗抗原具有生物治疗潜力,因此也是一个极具吸引力的靶点。本综述将重点介绍分泌型 NS1(sNS1)结构及其与单克隆抗体(mAbs)复合物的最新进展。据报道,NS1 在分泌时会形成六聚体(三聚体二聚体),可以解离并与上皮细胞膜结合。然而,关于 sNS1 的高阶低聚物状态的高分辨率结构信息一直缺失。后来的几项冷冻电镜研究表明,DENV 和 ZIKV 重组 sNS1(rsNS1)处于二聚体-四聚体-六聚体的动态平衡状态,其中四聚体是最主要的形式。最近有研究发现,感染衍生的 sNS1(isNS1)形成了一个部分嵌入高密度脂蛋白(HDL)颗粒的 NS1 二聚体复合物。还有报道称,NS1 与 mAbs 复合物的结构揭示了它们在感染过程中的保护作用。NS1低聚物状态多样性的生物学意义仍有待进一步研究,以便为今后的黄病毒致病机理研究以及治疗药物和疫苗的开发提供信息。鉴于黄病毒 NS1 在不同样本类型中的多态性以及抗原性的变化,我们提出了一种命名法,以根据定位和来源准确定义 NS1。
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引用次数: 0
JNJ-7184, a respiratory syncytial virus inhibitor targeting the connector domain of the viral polymerase JNJ-7184 是一种针对病毒聚合酶接头结构域的呼吸道合胞病毒抑制剂。
IF 7.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-05-19 DOI: 10.1016/j.antiviral.2024.105907
Brecht Bonneux , Afzaal Shareef , Sergey Tcherniuk , Brandon Anson , Suzanne de Bruyn , Nick Verheyen , Kim Thys , Nádia Conceição-Neto , Marcia Van Ginderen , Leen Kwanten , Nina Ysebaert , Luc Vranckx , Elien Peeters , Ellen Lanckacker , Jack M. Gallup , Panchan Sitthicharoenchai , Sarhad Alnajjar , Mark R. Ackermann , Suraj Adhikary , Anusarka Bhaumik , Florence Herschke

Respiratory syncytial virus (RSV) can cause pulmonary complications in infants, elderly and immunocompromised patients. While two vaccines and two prophylactic monoclonal antibodies are now available, treatment options are still needed. JNJ-7184 is a non-nucleoside inhibitor of the RSV-Large (L) polymerase, displaying potent inhibition of both RSV-A and -B strains. Resistance selection and hydrogen-deuterium exchange experiments suggest JNJ-7184 binds RSV-L in the connector domain. JNJ-7184 prevents RSV replication and transcription by inhibiting initiation or early elongation. JNJ-7184 is effective in air-liquid interface cultures and therapeutically in neonatal lambs, acting to drastically reverse the appearance of lung pathology.

呼吸道合胞病毒(RSV)可导致婴儿、老年人和免疫力低下患者出现肺部并发症。虽然目前已有两种疫苗和两种预防性单克隆抗体,但仍需要治疗方案。JNJ-7184 是 RSV-Large (L) 聚合酶的非核苷抑制剂,对 RSV-A 和 -B 株都有很强的抑制作用。抗药性选择和氢氘交换实验表明,JNJ-7184 能在连接域结合 RSV-L。JNJ-7184 通过抑制起始或早期延伸来阻止 RSV 复制和转录。JNJ-7184 在气液界面培养和新生羔羊治疗中都很有效,能显著逆转肺部病变的出现。
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引用次数: 0
Cytomegalovirus UL44 protein induces a potent T-cell immune response in mice 巨细胞病毒 UL44 蛋白可诱导小鼠产生强烈的 T 细胞免疫反应。
IF 7.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-05-15 DOI: 10.1016/j.antiviral.2024.105914
Francisco J. Mancebo , Marcos Nuévalos , Jaanam Lalchandani , Antonio J. Martín Galiano , Mario Fernández-Ruiz , José María Aguado , Estéfani García-Ríos , Pilar Pérez-Romero

Due to the severity of CMV infection in immunocompromised individuals the development of a vaccine has been declared a priority. However, despite the efforts made there is no yet a vaccine available for clinical use. We designed an approach to identify new CMV antigens able to inducing a broad immune response that could be used in future vaccine formulations.

We have used serum samples from 28 kidney transplant recipients, with a previously acquired CMV-specific immune response to identify viral proteins that were recognized by the antibodies present in the patient serum samples by Western blot. A band of approximately 45 kDa, identified as UL44, was detected by most serum samples. UL44 immunogenicity was tested in BALB/c mice that received three doses of the UL44-pcDNA DNA vaccine. UL44 elicited both, a strong antibody response and CMV-specific cellular response. Using bioinformatic analysis we demonstrated that UL44 is a highly conserved protein and contains epitopes that are able to activate CD8 lymphocytes of the most common HLA alleles in the world population. We constructed a UL44 ORF deletion mutant virus that produced no viral progeny, suggesting that UL44 is an essential viral protein. In addition, other authors have demonstrated that UL44 is one of the most abundant viral proteins after infection and have suggested an essential role of UL44 in viral replication. Altogether, our data suggests that UL44 is a potent antigen, and favored by its abundance, it may be a good candidate to include in a vaccine formulation.

由于巨细胞病毒感染对免疫力低下者的严重影响,疫苗的开发已被列为当务之急。然而,尽管已经做出了很多努力,但目前还没有可用于临床的疫苗。我们设计了一种方法来识别能诱导广泛免疫反应的新 CMV 抗原,以用于未来的疫苗配方。我们使用了 28 位肾移植受者的血清样本,通过 Western 印迹法鉴定了患者血清样本中抗体可识别的病毒蛋白。大多数血清样本中都检测到了一条大约 45 kDa 的条带,被确定为 UL44。在接种了三剂 UL44-pcDNA DNA 疫苗的 BALB/c 小鼠中测试了 UL44 的免疫原性。UL44 可引起强烈的抗体反应和 CMV 特异性细胞反应。通过生物信息学分析,我们证明了 UL44 是一种高度保守的蛋白质,它包含的表位能够激活世界人口中最常见的 HLA 等位基因的 CD8 淋巴细胞。我们构建的 UL44 ORF 缺失突变病毒不产生病毒后代,这表明 UL44 是一种重要的病毒蛋白。此外,其他作者也证明 UL44 是感染后含量最高的病毒蛋白之一,并认为 UL44 在病毒复制中起着重要作用。总之,我们的数据表明,UL44 是一种强效抗原,由于其含量丰富,它可能是疫苗配方中的理想候选抗原。
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引用次数: 0
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 & PHARMACY 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 & PHARMACY 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 & PHARMACY 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 & PHARMACY 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 & PHARMACY 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 & PHARMACY 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。
{"title":"Characterization of SARS-CoV-2 replication in human H1299/ACE2 cells: A versatile and practical infection model for antiviral research and beyond","authors":"Clarisse Salgado-Benvindo ,&nbsp;Ali Tas ,&nbsp;Jessika C. Zevenhoven-Dobbe ,&nbsp;Yvonne van der Meer ,&nbsp;Igor A. Sidorov ,&nbsp;Anouk A. Leijs ,&nbsp;Patrick Wanningen ,&nbsp;Anne T. Gelderloos ,&nbsp;Puck B. van Kasteren ,&nbsp;Eric J. Snijder ,&nbsp;Martijn J. van Hemert","doi":"10.1016/j.antiviral.2024.105903","DOIUrl":"10.1016/j.antiviral.2024.105903","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"227 ","pages":"Article 105903"},"PeriodicalIF":7.6,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0166354224001128/pdfft?md5=92fc4a305322f2a32bfbc7a993302019&pid=1-s2.0-S0166354224001128-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140896993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Antiviral research
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