Antiviral research最新文献

Nucleotide analogues and Mpox : Repurposing the repurposable.

IF 4.5 2区医学

Antiviral research Pub Date : 2024-12-16 DOI: 10.1016/j.antiviral.2024.106057

Ashleigh Shannon, Bruno Canard

{"title":"Nucleotide analogues and Mpox : Repurposing the repurposable.","authors":"Ashleigh Shannon, Bruno Canard","doi":"10.1016/j.antiviral.2024.106057","DOIUrl":"https://doi.org/10.1016/j.antiviral.2024.106057","url":null,"abstract":"<p><p>While the COVID-19 crisis is still ongoing, a new public health threat has emerged with recent outbreaks of monkeypox (mpox) infections in Africa. Mass vaccination is not currently recommended by the World Health Organization (WHO), and antiviral treatments are yet to be specifically approved for mpox, although existing FDA-approved drugs (Tecovirimat, Brincidofovir, and Cidofovir) may be used in severe cases or for immunocompromised patients. A first-line of defense is thus drug repurposing, which was heavily attempted against SARS-CoV-2 - albeit with limited success. This review focuses on nucleoside analogues as promising antiviral candidates for targeting of the viral DNA-dependent DNA polymerase. In contrast to broad-spectrum screening approaches employed for SARS-CoV-2, we emphasize the importance of understanding the structural specificity of viral polymerases for rational selection of potential candidates. By comparing DNA-dependent DNA polymerases with other viral polymerases, we highlight the unique features that influence the efficacy and selectivity of nucleoside analogues. These structural insights provide a framework for the preselection, repurposing, optimization, and design of nucleoside analogues, aiming to accelerate the development of targeted antiviral therapies for mpox and other viral infections.</p>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106057"},"PeriodicalIF":4.5,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pellino-1, a therapeutic target for control of SARS-CoV-2 infection and disease severity.

IF 4.5 2区医学

Antiviral research Pub Date : 2024-12-15 DOI: 10.1016/j.antiviral.2024.106059

Binbin Wang, Hongjie Xia, Bi-Hung Peng, Eun-Jin Choi, Bing Tian, Xuping Xie, Shinji Makino, Xiaoyong Bao, Pei-Yong Shi, Vineet Menachery, Tian Wang

{"title":"Pellino-1, a therapeutic target for control of SARS-CoV-2 infection and disease severity.","authors":"Binbin Wang, Hongjie Xia, Bi-Hung Peng, Eun-Jin Choi, Bing Tian, Xuping Xie, Shinji Makino, Xiaoyong Bao, Pei-Yong Shi, Vineet Menachery, Tian Wang","doi":"10.1016/j.antiviral.2024.106059","DOIUrl":"10.1016/j.antiviral.2024.106059","url":null,"abstract":"<p><p>Enhanced expression of Pellino-1 (Peli1), a ubiquitin ligase is known to be associated with COVID-19 susceptibility. The underlying mechanisms are not known. Here, we report that mice deficient in Peli1 (Peli1<sup>-/-</sup>) had reduced viral load and attenuated inflammatory immune responses and tissue damage in the lung following SARS-CoV-2 infection. Overexpressing Peli1 in 293 T cells increased SARS-CoV-2 infection via promoting virus replication and transcription, without affecting virus attachment and entry into the cells. Smaducin-6 treatment which is known to disrupt Peli1-mediated NF-KB activation, attenuated inflammatory immune responses in human lung epithelial cells as well as in the lung of K18-hACE2 mice following SARS-CoV-2 infection, though it had minimal effects on SARS-CoV-2 infection in human nasal epithelial cells. Overall, our findings suggest that Peli1 contributes to SARS-CoV-2 pathogenesis by promoting virus replication and positively regulating virus-induced inflammatory responses in lung epithelial cells. Peli1 is a therapeutic target to control SARS-CoV-2 -induced disease severity.</p>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106059"},"PeriodicalIF":4.5,"publicationDate":"2024-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

Antiviral research Pub Date : 2024-12-11 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

{"title":"Construction of a recombinant African swine fever virus with firefly luciferase and eGFP reporter genes and its application in high-throughput antiviral drug screening.","authors":"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","doi":"10.1016/j.antiviral.2024.106058","DOIUrl":"10.1016/j.antiviral.2024.106058","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106058"},"PeriodicalIF":4.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142821854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Negative regulation of SREBP-1/FAS signaling molecules activates the RIG-1/TBK1-mediated IFN-I pathway to inhibit BVDV replication.

IF 4.5 2区医学

Antiviral research Pub Date : 2024-12-09 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

{"title":"Negative regulation of SREBP-1/FAS signaling molecules activates the RIG-1/TBK1-mediated IFN-I pathway to inhibit BVDV replication.","authors":"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","doi":"10.1016/j.antiviral.2024.106054","DOIUrl":"10.1016/j.antiviral.2024.106054","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106054"},"PeriodicalIF":4.5,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Antiviral Drug Discovery with an Optimized Biochemical Dengue Protease Assay: Improved Predictive Power for Antiviral Efficacy.

IF 4.5 2区医学

Antiviral research Pub Date : 2024-12-05 DOI: 10.1016/j.antiviral.2024.106053

Johannes Lang, Sudip Kumar Dutta, Mila M Leuthold, Lisa Reichert, Nikos Kühl, Byron Martina, Christian D Klein

{"title":"Antiviral Drug Discovery with an Optimized Biochemical Dengue Protease Assay: Improved Predictive Power for Antiviral Efficacy.","authors":"Johannes Lang, Sudip Kumar Dutta, Mila M Leuthold, Lisa Reichert, Nikos Kühl, Byron Martina, Christian D Klein","doi":"10.1016/j.antiviral.2024.106053","DOIUrl":"https://doi.org/10.1016/j.antiviral.2024.106053","url":null,"abstract":"<p><p>The viral NS2B-NS3 protease is a promising drug target to combat dengue virus (DENV) and other emerging flaviviruses. The discovery of novel DENV protease inhibitors with antiviral efficacy is hampered by the low predictive power of biochemical assays. We herein present a comparative evaluation of biochemical DENV protease assay conditions and their benchmarking against antiviral efficacy and a protease-specific reporter gene assay. Variations were performed with respect to pH, type of detergent, buffer, and substrate. The revised assay conditions were applied in a medicinal chemistry effort aimed at phenylglycine protease inhibitors. This validation study demonstrated a considerably improved predictive power for antiviral efficacy in comparison to previous approaches. An extensive evaluation of phenylglycine-based DENV protease inhibitors with highly diverse N-terminal caps indicates further development potential in this structural region. Furthermore, the phenylglycine moiety may be less essential than previously assumed, providing a development option towards reduced lipophilicity and thereby an improved pharmacokinetic and toxicity profile.</p>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106053"},"PeriodicalIF":4.5,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibitors of dihydroorotate dehydrogenase synergize with the broad antiviral activity of 4'-fluorouridine.

IF 4.5 2区医学

Antiviral research Pub Date : 2024-12-03 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

{"title":"Inhibitors of dihydroorotate dehydrogenase synergize with the broad antiviral activity of 4'-fluorouridine.","authors":"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","doi":"10.1016/j.antiviral.2024.106046","DOIUrl":"10.1016/j.antiviral.2024.106046","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106046"},"PeriodicalIF":4.5,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

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

{"title":"Edible bird's nest: N- and O-glycan analysis and synergistic anti-avian influenza virus activity with neuraminidase inhibitors","authors":"Nongluk Sriwilaijaroen , Hisatoshi Hanamatsu , Ikuko Yokota , Takashi Nishikaze , Tetsuo Ijichi , Tadanobu Takahashi , Yoshihiro Sakoda , Jun-ichi Furukawa , Yasuo Suzuki","doi":"10.1016/j.antiviral.2024.106040","DOIUrl":"10.1016/j.antiviral.2024.106040","url":null,"abstract":"<div><div>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 <em>N</em>-glycans (N-35) and di-α2,3Neu5Ac core 2 <em>O</em>-glycans (O-15) are predominant, accounting for 53.46% and 44.66% of total <em>N</em>- and <em>O</em>-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.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"232 ","pages":"Article 106040"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

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

{"title":"Preventing human influenza and coronaviral mono or coinfection by blocking virus-induced sialylation","authors":"Md Ruhul Amin , Khandaker N. Anwar , M.J. Ashraf , Mahmood Ghassemi , Richard M. Novak","doi":"10.1016/j.antiviral.2024.106041","DOIUrl":"10.1016/j.antiviral.2024.106041","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"232 ","pages":"Article 106041"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708945","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

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.

IF 4.5 2区医学

Antiviral research Pub Date : 2024-12-01 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

{"title":"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.","authors":"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","doi":"10.1016/j.antiviral.2024.106045","DOIUrl":"10.1016/j.antiviral.2024.106045","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106045"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

Antiviral research Pub Date : 2024-12-01 Epub Date: 2024-11-23 DOI: 10.1016/j.antiviral.2024.106042

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

{"title":"Development of lipopeptide-based HIV-1/2 fusion inhibitors targeting the gp41 pocket site with a new design strategy.","authors":"Xiuzhu Geng, Yuanmei Zhu, Yue Gao, Huihui Chong, Yuxian He","doi":"10.1016/j.antiviral.2024.106042","DOIUrl":"10.1016/j.antiviral.2024.106042","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106042"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0