Antiviral research最新文献

{"title":"Optimization of the monoclonal antibody 3E1 through W32I mutation enhances antiviral efficacy against influenza virus subtypes H1N1 and H3N2","authors":"Shanshan Guan ,&nbsp;Qingyu Wang ,&nbsp;Jiaojiao Nie ,&nbsp;Xin Yao ,&nbsp;Kunpeng Xie ,&nbsp;Weihao Zhao ,&nbsp;Yaotian Chang ,&nbsp;Lvzhou Zhu ,&nbsp;Jiaru Hui ,&nbsp;Tieyan Yin ,&nbsp;Xiaopan Liu ,&nbsp;Yingxin Zhang ,&nbsp;Yaming Shan","doi":"10.1016/j.antiviral.2025.106260","DOIUrl":"10.1016/j.antiviral.2025.106260","url":null,"abstract":"<div><div>The influenza virus has caused a global pandemic with significant morbidity and mortality, underscoring the need to optimize antibodies for improved antiviral efficacy. The monoclonal antibody 3E1 effectively neutralizes Group 1 influenza subtypes, H1 and H5, by inhibiting acid-induced conformational changes of hemagglutinin (HA). However, its neutralizing activity is relatively weak against the Group 2 subtype, H3. In order to broaden the neutralizing activity of wild-type 3E1 (3E1-WT) against both Group 1 and Group 2 viral strains, single-point mutants (3E1-L [W32I], 3E1-H [F103I]) and a double mutant (3E1-H + L [F103I, W32I]) were designed and generated in this study. The binding affinity, microneutralizing activity, and antiviral mechanisms of the mutants were evaluated <em>in vitro</em>. Notably, the 3E1-L mutant exhibited significantly enhanced antiviral activity against H1N1 and H3N2 compared to 3E1-WT, inhibiting both viral entry and release. <em>In vivo</em> studies also indicate that 3E1-L significantly enhances both prophylactic and therapeutic efficacy against A/New-York/61/2015-CDC-LV16A (H1N1) and A/Hong Kong/17/2014/8296 (H3N2). Molecular dynamics simulations of the 3E1-L/HA complex revealed that the W32I mutation could reduce steric hindrance between tryptophan at position 32 and the complementarity-determining region L1 loop of HA. In conclusion, the W32I substitution enhances the antiviral activity of 3E1-WT, suggesting that the optimization of 3E1-L a promising strategy for the development of more effective influenza therapy and prevention.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"242 ","pages":"Article 106260"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862065","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}

{"title":"SMAD5 phosphorylation by ALK1 is modulated by the interaction of the spike protein of SARS-CoV-2 and angiotensin-converting enzyme 2","authors":"Yoichi Teratake ,&nbsp;Tadashi Okamura ,&nbsp;Yukihito Ishizaka","doi":"10.1016/j.antiviral.2025.106261","DOIUrl":"10.1016/j.antiviral.2025.106261","url":null,"abstract":"<div><div>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 7 million worldwide deaths, but the mechanisms underlying its severe clinical outcomes remain elusive. Although attachment of the spike (S) protein of SARS-CoV-2 to angiotensin-converting enzyme 2 (ACE2), a pivotal step for infection, induces inflammation, the intracellular signals triggered by this interaction are unclear. Here, we found that S protein induced phosphorylation of SMAD family member 5 which was mediated by the bone morphologenetic protein (BMP) receptor activin receptor-like kinase 1 (ALK1) and BMP receptor type II. SMAD5 activation depended on the interaction of the cytoplasmic domains of ACE2 and ALK1. Notably, repetitive treatment with S protein increased the expression of immune-response genes, including interferon regulatory factor 1, interleukin-17A, and cysteine-cysteine chemokine motif ligand 20 (CCL20), all of which were blocked by an ALK inhibitor. In contrast, the S protein of human coronavirus NL63, a pathogen of acute respiratory infection with less severity than SARS-CoV-2 that also binds to ACE2, did not activate SMAD5. Because CCL20 recruits multiple immune cells positive for CC receptor 6, a specific receptor for CCL20, and was detected in broncho-alveolar lavage fluids of patients with respiratory failures by SARS-Cov-2, data suggest that SMAD5 activation by S protein augments the early immune response, leading to the severe clinical outcomes of SARS-CoV-2.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"242 ","pages":"Article 106261"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144889792","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}

{"title":"Modeling neurotropic virus infection with functional human neural spheroids as a platform for high-throughput antiviral screening and pathogenesis.","authors":"Angelica Medina, Yu-Chi Chen, Jiajing Zhang, Sarah C Ogden, Samantha Cotsmire, Harshad D Vishwasrao, Marc Ferrer, Emily M Lee","doi":"10.1016/j.antiviral.2025.106248","DOIUrl":"10.1016/j.antiviral.2025.106248","url":null,"abstract":"<p><p>Neurotropic arboviruses pose significant threats to human health due to their ability to infect the central nervous system (CNS). Despite the significant impact on public health, mechanisms underlying neuropathogenesis remains poorly understood, and the development of effective antivirals has been hampered by the lack of predictive, high-throughput (HT) infection platforms that can replicate in vivo disease features to drive early drug discovery. To address this gap, we developed a human-based, HT-compatible, functional viral disease neural spheroid model assembled from human induced pluripotent stem cell (hiPSC)-differentiated neurons and astrocytes as a platform for studying virus infection and the development of HT screening (HTS)-compatible assays for drug discovery. Here, we investigated eight high impact species belonging to either the Bunyaviricetes class or Togaviridae family and evaluated infectability on neural spheroids, followed by characterization of neural activity dysregulation and induced disease. We found that neural spheroids support productive infection, with virus- and time-dependent changes in disease profiles. Transcriptomic changes induced by two representative members, LACV and CHIKV, revealed a highly pro-inflammatory response in LACV infected spheroids whereas CHIKV-infection induced neurodegenerative profiles. Finally, we evaluated antiviral and anti-neural dysfunction activity of interferon-alpha as well as tested the small molecule gemcitabine against CHIKV as a proof-of-concept for HT antiviral compound screening. Together, our data establishes the viral-neural spheroids as a valuable platform that supports productive infection by high impact neurotropic viruses, and this platform can be used to both investigate viral pathogenesis and support therapeutics discovery and development.</p>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106248"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774555","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}

{"title":"Characterization of remdesivir resistance mutations in COVID-19 patients with various immunosuppressive diseases","authors":"Takaya Ichikawa ,&nbsp;Tomokazu Tamura ,&nbsp;Naganori Nao ,&nbsp;Hikoyu Suzuki ,&nbsp;Shuhei Maruyama ,&nbsp;Daiki Wada ,&nbsp;Shuhei Tsujino ,&nbsp;Noriyoshi Yoshinaga ,&nbsp;Kohsuke Asagoe ,&nbsp;Mutsumi Takahata ,&nbsp;Takashi Ishio ,&nbsp;Makoto Ibata ,&nbsp;Tanino Yoko ,&nbsp;Yasutaka Kakinoki ,&nbsp;Kazuhiro Okubo ,&nbsp;Rigel Suzuki ,&nbsp;Saori Suzuki ,&nbsp;Yasushi Nakamori ,&nbsp;Takanori Teshima ,&nbsp;Takasuke Fukuhara","doi":"10.1016/j.antiviral.2025.106264","DOIUrl":"10.1016/j.antiviral.2025.106264","url":null,"abstract":"<div><div>Immunocompromised patients (ICPs), such as those who receive certain immunosuppressive therapies, occasionally experience prolonged viral infections even after antiviral treatment. In some cases, antiviral-resistant viruses may eventually emerge. Remdesivir (RDV) is an adenosine nucleoside analog that inhibits the activity of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA polymerase, which is composed of a catalytic subunit known as nsp12. Previous studies have reported that amino acid mutations around loci 790–810 in nsp12 are responsible for RDV resistance. However, the host immune status that promotes the emergence of resistant viruses and their virological features remain unclear. We therefore collected clinical samples from 15 coronavirus disease 2019 (COVID-19) patients with various immunosuppressive conditions who received RDV. Variant analysis identified a total of seven nsp12 mutations—V792I, M794I, E796D, E796K, C799F, C799Y, and T803I—in 80 % (12/15) of the participants, with M794I and V792I the most prevalent. The identified mutations were more frequently observed in severely ICPs (including patients with hematological malignancies or kidney transplantation) compared to non-severely ICPs (including patients with solid cancers or autoimmune diseases). <em>In vitro</em> analysis using recombinant viruses carrying each identified mutation demonstrated that all mutant viruses were less efficient in growth compared to wildtype but with a 1.8-fold (T803I) to 3.6-fold (V792I) increase in the half maximal effective concentration (EC₅₀) of RDV. The present study highlights the importance of monitoring resistance mutations to anti–SARS-CoV-2 drugs in severely ICPs.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"242 ","pages":"Article 106264"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144916472","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}

{"title":"N-myristoyltransferase inhibitors as candidate broad-spectrum antivirals to treat viral infections promoted by immunosuppression associated with JAK inhibitors therapy","authors":"Haydar Witwit,&nbsp;Juan C. de la Torre","doi":"10.1016/j.antiviral.2025.106258","DOIUrl":"10.1016/j.antiviral.2025.106258","url":null,"abstract":"<div><div>The use of Janus kinase (JAK) inhibitors in the clinic has been expanded significantly during the last decade. However, the immunosuppressive effects of JAK inhibitors, via modulation of key innate cellular signaling pathways, can predispose treated patients to infections, and can also result in reduced control of silent infections and increased risk of reactivation of opportunistic infections. Thus, the JAK inhibitor ruxolitinib, approved for the treatment of myelofibrosis and polycythemia vera, has been shown to exerts a proviral activity during infection with different viruses. Therefore, the clinical relevance of developing antiviral treatments that can be effective in the presence of JAK inhibitors. N-terminal myristoyl transferase (NMT) inhibitors have been shown to exhibit potent antiviral activity against different viruses. Here we document that in the presence of ruxolitinib, NMT inhibitors retain their potent antiviral activity against different viruses, including HSV-1. Our findings support that NMT inhibitors should be explored as therapeutics to treat viral infections associated with immunosuppression caused by treatments with JAK inhibitors.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"242 ","pages":"Article 106258"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144844301","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}

{"title":"Dexamethasone treatment does not alter mortality but reduces pulmonary pathology in Nipah virus-infected Syrian hamsters","authors":"Kerry Goldin ,&nbsp;Bridget Brackney ,&nbsp;Tessa Lutterman ,&nbsp;Brandi N. Williamson ,&nbsp;Manmeet Singh ,&nbsp;Christopher Winski ,&nbsp;Kathleen Cordova ,&nbsp;Meaghan Flagg ,&nbsp;Emmie de Wit","doi":"10.1016/j.antiviral.2025.106263","DOIUrl":"10.1016/j.antiviral.2025.106263","url":null,"abstract":"<div><div>Nipah virus (NiV) is an emerging zoonotic pathogen that causes severe respiratory and neurologic disease, and there are currently no licensed vaccines or approved treatments. The acute respiratory disease caused by NiV is associated with severe inflammation, similar to severe COVID-19. Dexamethasone is an affordable and widely available synthetic glucocorticoid, that improved outcomes when administered to patients with severe COVID-19. To determine whether a similar beneficial effect could be achieved during NiV infection, we tested the effect of an anti-inflammatory or immunosuppressive dose of dexamethasone on NiV in the Syrian hamster model. We found that dexamethasone treatment produced the expected hematologic changes in uninfected animals in a dose-dependent manner. In NiV-infected animals, the anti-inflammatory dose of dexamethasone reduced pulmonary pathology, while the immunosuppressive dose had no effect. The anti-inflammatory dose did not increase virus replication in tissues or virus shedding from the respiratory tract, indicating the anti-inflammatory dose of dexamethasone does not result in increased virus replication. Despite reduced lung pathology, dexamethasone treatment did not increase survival after NiV challenge. When dexamethasone treatment was combined with the antiviral remdesivir, dexamethasone negated the increased survival observed in hamsters treated with remdesivir alone. Our study provides critical information on the effect of dexamethasone administration on the outcome of NiV infection and cautions against the use of dexamethasone in combination with other antivirals like remdesivir without preclinical validation.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"242 ","pages":"Article 106263"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144885972","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}

{"title":"An engineered chimeric ACE2-HR2 peptide exhibits potent and broad-spectrum activity against SARS-CoV-2 variants","authors":"Wenwen Bi ,&nbsp;Tao Zhu ,&nbsp;Yawen Xu ,&nbsp;Yihui Chen ,&nbsp;Jianmin Li","doi":"10.1016/j.antiviral.2025.106265","DOIUrl":"10.1016/j.antiviral.2025.106265","url":null,"abstract":"<div><div>The persistent circulation of SARS-CoV-2 and limited efficacy of current vaccines in preventing viral transmission underscore the critical need for broad-spectrum antivirals. Here, we report a novel engineering strategy to develop A3M6L35HR2 (FL), a cholesterol-free recombinant peptide derived from our previously reported A1L35HR2, by incorporating an optimized angiotensin-converting enzyme 2 (ACE2)-mimetic peptide A3M6 with six residue mutations. A3M6L35HR2 (FL) exhibited superior inhibitory potency against diverse SARS-CoV-2 variants with IC₅₀ from 1.7 to 16.2 nM, including antigenically distinct Omicron sublineages, achieving 2- to 29-fold enhanced activity compared to A1L35HR2. A3M6L35HR2 (FL) exhibits a higher α-helicity (70 %) and stronger binding affinity (K_D = 0.03 nM) with the viral HR1 domain, thereby effectively suppressing spike-mediated membrane fusion at nanomolar concentrations. Combining A3M6L35HR2 (FL) with RBD-targeting protein T-ACE2 exhibited antagonistic effect, attributed to competitive RBD binding by both agents. These findings establish A3M6L35HR2 (FL) as a promising antiviral candidate against current and emerging SARS-CoV-2 variants.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"242 ","pages":"Article 106265"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144916471","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}

{"title":"Viral determinants of cis- and trans-cleavage by SARS-CoV-2 Nsp3 and an on-off reporter for monitoring intracellular protease activity","authors":"Fuzhi Lei ,&nbsp;Jun Shu ,&nbsp;Chengjie Xia ,&nbsp;Yahan Lei ,&nbsp;Yajie Zhang ,&nbsp;Yang Zhang ,&nbsp;Zhenghong Yuan ,&nbsp;Zhigang Yi","doi":"10.1016/j.antiviral.2025.106262","DOIUrl":"10.1016/j.antiviral.2025.106262","url":null,"abstract":"<div><div>Non-structural protein 3 (nsp3), the largest multifunctional membrane-associated protein encoded by coronaviruses, contains a papain-like protease (PLpro) domain that cleaves viral polypeptides at the nsp1/nsp2, nsp2/nsp3 and nsp3/nsp4 junctions, as well as host substrates such as polyubiquitin chains and ISG15. While host substrate recognition by PLpro is well characterized, the processes by which PLpro identifies and interacts with membrane-associated viral substrates remains poorly defined. In this study, we developed full-length nsp3-containg reporter constructs to investigate PLpro-mediated cleavage in a membrane context. Our results show that differential cleavage sensitivity at nsp2/3 nsp3/4 junction in response to protein expression levels: nsp2/3 cleavage occurred even at low expression levels, whereas efficient nsp3/4 cleavage required high protein dosage, suggesting a reliance on <em>trans</em>-cleavage for the latter. Mutagenesis and structural analysis based on the recently resolved nsp3-4 complex structure suggest that membrane constraints on the substrate, along with positional and conformational requirements of the PLpro domain for <em>cis</em>-cleavage, contribute to the trans-cleavage preference at the nsp3/4 site. Membrane localization and specific protein-protein interactions further facilitate this <em>trans</em>-cleavage process. To assess nsp3/4 cleavage in a more physiologically relevant context, we developed a cleavage-induced degron (CID) system that mimics authentic viral polyprotein processing. This system generates a binary signal upon cleavage at the nsp3/4 junction and response to inhibition by the PLpro inhibitor GRL-0617. Our findings reveal that the domain arrangement of nsp3 dictates trans-dependence of the nsp3/4 cleavage, involving membrane association and protein interactions that may facilitate the subsequent double-membrane vesicle assembly.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"242 ","pages":"Article 106262"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144879370","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}

{"title":"Global update on the susceptibilities of influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2020–2023","authors":"Saira Hussain ,&nbsp;Adam Meijer ,&nbsp;Elena A. Govorkova ,&nbsp;Clyde Dapat ,&nbsp;Larisa V. Gubareva ,&nbsp;Ian G. Barr ,&nbsp;Sook Kwan Brown ,&nbsp;Rod S. Daniels ,&nbsp;Seiichiro Fujisaki ,&nbsp;Monica Galiano ,&nbsp;Weijuan Huang ,&nbsp;Rebecca J. Kondor ,&nbsp;Angie Lackenby ,&nbsp;Nicola Lewis ,&nbsp;Janice Lo ,&nbsp;Ha T. Nguyen ,&nbsp;Mira C. Patel ,&nbsp;Dmitriy Pereyaslov ,&nbsp;Aine Rattigan ,&nbsp;Magdi Samaan ,&nbsp;Emi Takashita","doi":"10.1016/j.antiviral.2025.106217","DOIUrl":"10.1016/j.antiviral.2025.106217","url":null,"abstract":"<div><div>Antiviral susceptibility of influenza viruses is monitored by the World Health Organization Global Influenza Surveillance and Response System. This study describes a global analysis of the susceptibility of influenza viruses to neuraminidase (NA) inhibitors (NAIs, oseltamivir, zanamivir, peramivir, laninamivir) and the cap-dependent endonuclease inhibitor (CENI, baloxavir) for three periods (May to May for 2020–2021, 2021–2022 and 2022–2023). In particular, global influenza activity declined significantly in 2020–2021 and 2021–2022 when compared to the pre-pandemic period of COVID-19. Combined phenotypic and NA sequence-based analysis revealed that the global frequency of seasonal influenza viruses with reduced or highly reduced inhibition (RI/HRI) by NAIs remained low, 0.09% (2/2224), 0.12% (27/23465) and 0.23% (124/53917) for 2020–2021, 2021–2022 and 2022–2023, respectively. As in previous years, NA-H275Y in A(H1N1)pdm09 viruses was the most frequent substitution causing HRI by oseltamivir and peramivir. Sequence-based analysis of polymerase acidic (PA) protein supplemented with phenotypic testing revealed low global frequencies of seasonal influenza viruses with reduced susceptibility (RS) to baloxavir, 0.07% (1/1376), 0.05% (9/18380) and 0.12% (48/39945) for 2020–2021, 2021–2022 and 2022–2023, respectively; commonly associated substitutions were PA-I38T/M/L. In Japan, the rate was 3.3% (16/488) during 2022–2023, with 11 A(H3N2) viruses having PA-I38T/M substitutions. For zoonotic viruses, 2.7% (3/111) contained substitutions, one each NA-H275Y, NA-S247N and NA-N295S, associated with RI/HRI NAI phenotypes, and none contained PA substitutions associated with RS to baloxavir. In conclusion, the great majority of seasonal and zoonotic influenza viruses remained susceptible to NAIs and CENI baloxavir.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"241 ","pages":"Article 106217"},"PeriodicalIF":4.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504680","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}

{"title":"The protease inhibitor Nirmatrelvir synergizes with inhibitors of GRP78 to suppress SARS-CoV-2 replication","authors":"Doha Al Krad ,&nbsp;Kim M. Stegmann ,&nbsp;Antje Dickmanns ,&nbsp;Priya Kumar ,&nbsp;Claudia Blaurock ,&nbsp;Björn-Patrick Mohl ,&nbsp;Sina Jasmin Wille ,&nbsp;Angele Breithaupt ,&nbsp;Tobias Britzke ,&nbsp;Anne Balkema-Buschmann ,&nbsp;Matthias Dobbelstein","doi":"10.1016/j.antiviral.2025.106247","DOIUrl":"10.1016/j.antiviral.2025.106247","url":null,"abstract":"<div><div>Nirmatrelvir, the active compound of the drug Paxlovid, inhibits the Main protease of SARS-CoV-2 (M^Pro, 3CL^Pro, NSP5). Its therapeutic application reduces but does not abolish the progression of COVID-19 in humans. Here we report a strong synergy of Nirmatrelvir with inhibitors of the ER chaperone GRP78 (HSPA5, BiP). Combining Nirmatrelvir with the GRP78-antagonizing drug candidate HA15 strongly inhibits the replication of SARS-CoV-2, to a far greater extent than either drug alone, as observed by diminished cytopathic effect, levels of detectable virus RNA, TCID₅₀ titers, and reduced accumulation of the non-structural proteins, as well as Spike and N proteins. The original SARS-CoV-2 strain as well as an Omicron variant were similarly susceptible towards the drug combination. Other GRP78 inhibitors or siRNAs targeting GRP78 also fortified the antiviral effect of Nirmatrelvir. In a hamster model of COVID-19, the combination of Nirmatrelvir with HA15 alleviated pneumonia-induced pulmonary atelectasis more effectively than the single drugs. In conclusion, inhibition of the virus Main protease and cellular GRP78 cooperatively diminishes virus replication and may improve COVID-19 therapy.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"241 ","pages":"Article 106247"},"PeriodicalIF":4.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759011","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}