Antiviral research最新文献

{"title":"Bemnifosbuvir and ruzasvir in combination exhibit potent synergistic antiviral activity in vitro while maintaining a favorable nonclinical safety profile in vivo","authors":"Steven S. Good,&nbsp;Shouqi Luo ,&nbsp;Kai Lin ,&nbsp;Alex Vo,&nbsp;Nancy G.B. Agrawal,&nbsp;Jean-Pierre Sommadossi","doi":"10.1016/j.antiviral.2025.106137","DOIUrl":"10.1016/j.antiviral.2025.106137","url":null,"abstract":"<div><div>Bemnifosbuvir (BEM), the orally available hemisulfate salt of the double prodrug of a guanosine nucleotide analog, is a potent, selective, and pan-genotypic inhibitor of HCV nonstructural protein 5B, an RNA-dependent RNA polymerase necessary for viral replication. Similarly, ruzasvir (RZR) is an orally available, highly potent, selective, and pan-genotypic inhibitor of HCV nonstructural protein 5A, an essential component of the viral replication complex. The antiviral effects of the combination of these two complementary direct-acting antivirals were determined in HCV GT1b Huh-7 replicon cells. Two independent <em>in vitro</em> evaluations suggested that BEM and RZR act synergistically to inhibit HCV replication without accompanying cytotoxicity. Additionally, the toxicity and toxicokinetic properties of BEM and RZR administered individually or in combination were investigated in rats given daily oral doses at 500 mg/kg of each drug for 13 weeks, with an interim analysis at 4 weeks. All doses were well tolerated with no test article-related adverse effects identified in either the separate or combined dose groups. Moreover, toxicokinetic analyses conducted on dose days 1, 28 and 84 indicated minimal pharmacokinetic interactions between the two drugs in rats, with AUC values for AT-511 (free base form of BEM), its major circulating metabolites, and RZR being similar, regardless of separate or co-administration.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"237 ","pages":"Article 106137"},"PeriodicalIF":4.5,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584490","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}

{"title":"Host-targeted repurposed diltiazem enhances the antiviral activity of direct acting antivirals against Influenza A virus and SARS-CoV-2","authors":"Blandine Padey ,&nbsp;Clément Droillard ,&nbsp;Victoria Dulière ,&nbsp;Julien Fouret ,&nbsp;Claire Nicolas de Lamballerie ,&nbsp;Cédrine Milesi ,&nbsp;Emilie Laurent ,&nbsp;Pauline Brun ,&nbsp;Aurélien Traversier ,&nbsp;Thomas Julien ,&nbsp;Olivier Terrier ,&nbsp;Manuel Rosa-Calatrava ,&nbsp;Andrés Pizzorno","doi":"10.1016/j.antiviral.2025.106138","DOIUrl":"10.1016/j.antiviral.2025.106138","url":null,"abstract":"<div><div>Viral respiratory infections remain a major and recurrent public health threat. Among them, influenza viruses are responsible for ⁓500,000 deaths worldwide and a high economic burden. The recurrent threat of emerging zoonotic or pandemic viruses worsens this scenario, being SARS-CoV-2 and the millions of COVID-19 deaths the most recent example. The rapid evolution of circulating influenza and SARS-CoV-2 viruses allows the emergence and dissemination of variant strains carrying mutations resulting in suboptimal vaccine protection and/or reduced efficacy of current limited therapeutic arsenal. In this context, host-targeted approaches constitute a promising antiviral strategy aiming to achieve broad-spectrum activity and mitigate the emergence of viral resistance against classic direct acting antivirals. Here, we demonstrated that diltiazem, a calcium channel blocker currently used to treat angor, induces an ISG expression profile characteristic of an antiviral cellular state mainly driven by IFN-λ. We then evaluated the potential of the diltiazem-baloxavir combination against Influenza A wild-type and the PA I38T resistant strain in cell culture and human airway epithelia (HAE). We analogously evaluated the diltiazem-molnupiravir combination against SARS-CoV-2, including variants of concern. Our results demonstrate the broad-spectrum antiviral activity of diltiazem against Influenza A viruses, including resistant strains, as well as the capacity to potentiate the antiviral effect of baloxavir. The diltiazem-molnupiravir combination further reduced viral production and protected the integrity of HAE infected with SARS-CoV-2. This study highlights the major interest of combining direct acting and host-targeted agents as a promising strategy against circulating and emerging viruses.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"237 ","pages":"Article 106138"},"PeriodicalIF":4.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143571926","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}

{"title":"Broad-spectrum antiviral ferruginol analog affects the viral proteins translation and actin remodeling during dengue virus infection","authors":"Vicky C. Roa-Linares ,&nbsp;Liliana A. Betancur-Galvis ,&nbsp;Miguel A. González-Cardenete ,&nbsp;Mariano A. Garcia-Blanco ,&nbsp;Juan C. Gallego-Gomez","doi":"10.1016/j.antiviral.2025.106139","DOIUrl":"10.1016/j.antiviral.2025.106139","url":null,"abstract":"<div><div>Dengue virus infection is the most important arbovirosis around the world. To date, no antiviral drugs have been approved for its treatment. Host-targeted antivirals (HTA) have emerged as a promising strategy, because of their high barrier to resistance. Using plaque-forming unit assays, molecular docking, fluorescence microscopy, image analysis, and molecular/cellular assays, it was found that 18-(phthalimide-2-yl)-ferruginol, a semi-synthetic analog of the bioactive diterpenoid ferruginol, couples with high affinity to RhoA GTPase. In addition, this molecule dramatically reduced actin filament formation and induced cellular morphological changes, when added to cell cultures before or after infection, without effect on microtubules or intermediate filaments. RhoA activation in infected cells was affected when the compound was added after 6 h.p.i. Furthermore, this compound decreased dengue virus-2 (DENV-2) E protein, NS3 protein, and dsRNA as measured by fluorescence microscopy, and changes in the distribution pattern of these viral components. 18-(phthalimide-2-yl)-ferruginol treatment at 6 and 12 h.p.i. reduces the virus yield. Western blot and RT-qPCR assays reveal that this analog decreased viral protein translation. Flow cytometry and wound-healing experiments also hint that cellular effects prompted for this compound do not relate to early apoptotic events and they could be reversible. Overall, our findings strongly suggest that 18-(phthalimide-2-yl)-ferruginol has an HTA mechanism, possibly disrupting the polyprotein translation of DENV-2 via alteration of RhoA-mediated actin remodeling and other related cellular and viral processes.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"237 ","pages":"Article 106139"},"PeriodicalIF":4.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562599","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":"GS-1 blocks entry of herpes viruses and more broadly inhibits enveloped viruses","authors":"E.A. Monson ,&nbsp;M.G. Lloyd ,&nbsp;R.I. Johnson ,&nbsp;K. Caracciolo ,&nbsp;J. Whan ,&nbsp;T.F. Rau ,&nbsp;S.L. Londrigan ,&nbsp;J.F. Moffat ,&nbsp;A.J. Mayfosh ,&nbsp;K.J. Helbig","doi":"10.1016/j.antiviral.2025.106136","DOIUrl":"10.1016/j.antiviral.2025.106136","url":null,"abstract":"<div><div>Varicella-Zoster Virus (VZV) and Herpes Simplex Virus (HSV) are significant global health concerns, infecting over 66% of the population. VZV causes varicella (chickenpox) and herpes zoster (shingles), while HSV leads to oral and genital herpes. Current antiviral treatments target viral replication but face limitations, such as the need for early intervention and the development of drug resistance, particularly in immunocompromised patients. Additionally, while shingles vaccines exist, their use is limited by availability, access, awareness, and cost. There is no vaccine for HSV. This study introduces GS-1, a novel formulation of undecylenic acid compounded with L-Arginine, as an entry inhibitor of enveloped viruses. In vitro studies demonstrate the antiviral activity of GS-1 against both VZV and HSV-1, with EC₅₀ values ranging from 26 μg/mL to 62 μg/mL. Additionally, GS-1 displayed antiviral activity against VZV in an <em>ex vivo</em> human skin model, indicating its potential as a topical antiviral agent. The unique mechanism of action of GS-1, which involved binding directly to viral particles and blocking viral entry, was also extended to another enveloped virus, zika virus (ZIKV), a member of the flavivirus family, but had limited ability to block the non-enveloped virus, rotavirus. GS-1 could offer an effective means of controlling viral infections, particularly when used as combination therapy with other antiviral agents. Future studies will focus on confirming these results in a clinical setting.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"237 ","pages":"Article 106136"},"PeriodicalIF":4.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143552163","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}

{"title":"Apatinib inhibits HTNV by stimulating TFEB-driven lysosome biogenesis to degrade viral protein","authors":"Qikang Ying ,&nbsp;Xiaoxiao Zhang ,&nbsp;Tianle Gu ,&nbsp;Junmei Zhang ,&nbsp;Yuhang Dong ,&nbsp;Wenjie Feng ,&nbsp;Dongjing Li ,&nbsp;Xingan Wu ,&nbsp;Fang Wang","doi":"10.1016/j.antiviral.2025.106124","DOIUrl":"10.1016/j.antiviral.2025.106124","url":null,"abstract":"<div><div><em>Hantaan Orthohantavirus</em> (Hantaan virus, HTNV) infection causes hemorrhagic fever with renal syndrome (HFRS) in humans, posing a significant health threat. Currently, there are no long-lasting protective vaccines or specific antivirals available, creating an urgent need for effective antiviral treatments in the clinical management of HFRS. Given that viruses exploit multiple host factors for their replication, host-oriented inhibitors could offer promising therapeutic options. In our study, we screened a library of 2570 drugs and identified apatinib, a kinase inhibitor, as a potent suppressor of HTNV infection both <em>in vitro</em> and <em>in vivo</em>. Mechanistic studies revealed that apatinib exerts its antiviral effect by targeting transcription factor EB (TFEB). Specifically, apatinib inhibits the PI3K-Akt signaling pathway and reduces mTOR phosphorylation, which in turn downregulates TFEB phosphorylation. This facilitates the nuclear translocation of TFEB and enhances lysosomal function by upregulating the expression of lysosome-associated genes and promoting lysosome biogenesis. Consequently, there is an increase in lysosome-mediated viral nucleocapsid protein degradation. The ability of apatinib to stimulate this lysosome-driven antiviral mechanism presents a potential new therapeutic approach for viral infections and offers valuable insights into virus-host interactions during HTNV replication.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"237 ","pages":"Article 106124"},"PeriodicalIF":4.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530926","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":"Structural and mechanistic insight into the phosphorylation reaction catalyzed by mpox virus thymidine kinase","authors":"Tenan Zhang ,&nbsp;Xiang Chen ,&nbsp;Chengcheng Tao ,&nbsp;Haojun Huang ,&nbsp;Zhi Luo ,&nbsp;Mengmeng Liu ,&nbsp;Wen Cui ,&nbsp;Wei Wang","doi":"10.1016/j.antiviral.2025.106125","DOIUrl":"10.1016/j.antiviral.2025.106125","url":null,"abstract":"<div><div>Mpox virus (MPXV) is the etiological agent of mpox, which is a major threat to human health. The identification of potential drug targets and the development of effective antiviral therapies are still urgently needed. The thymidine kinase (TK) encoded by MPXV initiates the deoxythymidine triphosphate (dTTP) salvage synthesis pathway and facilitates viral DNA replication. MPXV without TK presents significant replication defects. MPXV TK is also responsible for the activation of nucleos(t)ide analogs, which are an important class of antivirals. Despite its importance in the viral life cycle and antiviral development, the structure and catalytic mechanism of MPXV TK are not fully understood. Here, we determined the three-dimensional structure of an MPXV TK variant, in which the glutamic acid at position 83 was substituted with alanine. MPXV TK consists of two domains and forms a tetramer. One protomer binds dTTP with two lassos and a P-loop, while the other protomers are captured in apo-form. Mutation of residues near the dTTP-binding site significantly reduces the catalytic activity of MPXV TK, indicating the importance of these residues in substrate binding and/or catalysis. Specifically, E83 is found to play a crucial role in stabilizing dTTP and lasso II. A biochemical assay confirmed that dTTP functions as a feedback inhibitor of MPXV TK and its inhibitory potency was evaluated. These results may facilitate the discovery of specific inhibitors targeting TK to mitigate MPXV infections.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"237 ","pages":"Article 106125"},"PeriodicalIF":4.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143529655","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":"Assessment of repurposed compounds against coronaviruses highlights the antiviral broad-spectrum activity of host-targeting iminosugars and confirms the activity of potent directly acting antivirals","authors":"Juliane Brun ,&nbsp;Benediktus Yohan Arman ,&nbsp;Michelle L. Hill ,&nbsp;J.L. Kiappes ,&nbsp;Dominic S. Alonzi ,&nbsp;Laetitia L. Makower ,&nbsp;Karolina D. Witt ,&nbsp;Carina Gileadi ,&nbsp;Victor Rangel ,&nbsp;Raymond A. Dwek ,&nbsp;Annette von Delft ,&nbsp;Nicole Zitzmann","doi":"10.1016/j.antiviral.2025.106123","DOIUrl":"10.1016/j.antiviral.2025.106123","url":null,"abstract":"<div><div>The COVID-19 pandemic highlights the need for novel antiviral drug discovery approaches that could dramatically shorten timelines from compound discovery to clinical development. At the beginning of the pandemic, repurposing approaches were at the forefront of early research efforts to screen for antiviral activity against SARS-CoV-2 in over 2500 compounds. Here, we report cellular screening results of 100 FDA-approved and experimental compounds against SARS-CoV-2 in the human Calu-3 cell line. We observed 13 compounds showing antiviral activity against SARS-CoV-2, including seven FDA-approved compounds (remdesivir, boceprevir, amiloride, nafamostat, cisplatin, silmitasertib, and miglustat), and six compounds in pre-clinical and clinical development (tarloxotinib, lucerastat (<em>N</em>B-DGJ), M<em>O</em>N-DNJ, <em>N</em>AP-DNJ, <em>N</em>N-DGJ and <em>N</em>N-DNJ). Further, we observed that our screening hits include several host-targeting antivirals, namely iminosugars, that are largely non-toxic and offer a large therapeutic window. The most-developed iminosugar M<em>O</em>N-DNJ (UV-4B), which has been evaluated in a Phase 1 clinical trial, shows antiviral activity against SARS-CoV-2 wild type as well as alpha, beta, gamma, delta, and Omicron variants. Its activity also extended to another betacoronavirus HCoV OC43, but not alphacoronavirus HCoV 229E. Our cellular screening results add to the body of knowledge on antivirals against coronaviruses and confirm the antiviral efficacy of iminosugars in cellular assays using the human lung-cell line Calu-3.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"237 ","pages":"Article 106123"},"PeriodicalIF":4.5,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143498102","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}

{"title":"Oral 4′-fluorouridine rescues mice from advanced lymphocytic choriomeningitis virus infection","authors":"Jonna B. Westover ,&nbsp;Kie Hoon Jung ,&nbsp;Shuli Mao ,&nbsp;Alexander A. Kolykhalov ,&nbsp;Gregory R. Bluemling ,&nbsp;Michael G. Natchus ,&nbsp;George R. Painter ,&nbsp;Brian B. Gowen","doi":"10.1016/j.antiviral.2025.106122","DOIUrl":"10.1016/j.antiviral.2025.106122","url":null,"abstract":"<div><div>Lymphocytic choriomeningitis virus (LCMV) can cause severe, life-threatening infection and disease in organ transplant recipients and other immunocompromised individuals. Additionally, significant developmental and neurological disabilities, vision impairments, and miscarriages can occur as a direct result of LCMV infection during pregnancy. Currently, there are no approved antiviral drugs to protect at-risk populations. Here, we report on the potent in vitro activity of the 4′-fluorouridine (4′-FlU) ribonucleoside analog against several strains of LCMV, with EC₉₀ values in the low micromolar range. In vivo, oral once-daily 4′-FlU treatments provided robust efficacy in mice challenged with LCMV when administered as late as 5 days post-infection. Our findings extend the broad-spectrum antiviral capacity of 4′-FlU and support the compound's further development for treating LCMV and other severe arenavirus infections.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"237 ","pages":"Article 106122"},"PeriodicalIF":4.5,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490519","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":"Research progress of vimentin in viral infections","authors":"Jiawei Zheng ,&nbsp;Xue Li ,&nbsp;Guoqing Zhang ,&nbsp;Ying Ren ,&nbsp;Linzhu Ren","doi":"10.1016/j.antiviral.2025.106121","DOIUrl":"10.1016/j.antiviral.2025.106121","url":null,"abstract":"<div><div>Vimentin, a type III intermediate filament protein, has become a focal point in the research of viral infections. It participates in multiple crucial processes during the viral life cycle and the host's antiviral response. During viral entry, it may function as a receptor or co-receptor and interact with viral entry proteins, also influencing endocytic pathways. Furthermore, vimentin engages with replication complexes and modulates the intracellular environment in viral replication. Moreover, vimentin plays significant roles in immune responses and inflammatory reactions during viral infections. This review thoroughly analyzes the recent progress in understanding vimentin's functions during viral infections, covering aspects such as viral entry, replication, and the immune response to achieve a cohesive comprehension of the underlying mechanisms. The antiviral strategies based on vimentin are also discussed, aiming to promote the development of more effective preventive and treatment strategies for viral diseases.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"236 ","pages":"Article 106121"},"PeriodicalIF":4.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143453950","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 efficiency of high-throughput screening (HTS) and in-silico data analysis during medical emergencies: Identification of effective antiviral 3CLpro inhibitors","authors":"Debora Zian ,&nbsp;Daniela Iaconis ,&nbsp;Simone Nenci ,&nbsp;Alessandra Crusco ,&nbsp;Sanjeevani Tawde ,&nbsp;Mariangela Sodano ,&nbsp;Rocco Vitalone ,&nbsp;Ameya Raje ,&nbsp;Martina Palamini ,&nbsp;Daniele Carettoni ,&nbsp;Angela Molteni ,&nbsp;Candida Manelfi ,&nbsp;Valerio Tazzari ,&nbsp;Andrea Rosario Beccari ,&nbsp;Paolo Malune ,&nbsp;Stefania Maloccu ,&nbsp;Annalaura Paulis ,&nbsp;Angela Corona ,&nbsp;Salvatore Nieddu ,&nbsp;Silvano Coletti ,&nbsp;MariaPia Catalani","doi":"10.1016/j.antiviral.2025.106119","DOIUrl":"10.1016/j.antiviral.2025.106119","url":null,"abstract":"<div><div>The COVID-19 pandemic highlighted the importance of accelerating the drug discovery process. The 3-chymotrypsin-like protease (3CLpro) is a critical enzyme in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral replication process and was quickly identified as a prime target for drug development. This study leverages High-Throughput Screening (HTS) to identify novel 3CLpro inhibitors. We screened a different library of 325,000 compounds, leading to the discovery of two new chemical scaffolds with selective inhibitory activity against 3CLpro. <em>In-silico</em> analysis and further experimental validation, elucidated the binding modes and mechanisms of action, revealing a covalent inhibitor targeting the catalytic pocket and two allosteric inhibitors affecting the monomer/dimer equilibrium of 3CLpro. The identified compounds demonstrated significant antiviral activity in vitro, reducing SARS-CoV-2 replication in VeroE6 and Calu-3 cell lines. This study highlights the potential of combining HTS and computational approaches to accelerate the discovery of effective antiviral agents, suggesting a workflow to support the research and the design of effective therapeutic strategies.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"237 ","pages":"Article 106119"},"PeriodicalIF":4.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466735","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}