Pub Date : 2025-11-01Epub Date: 2025-09-04DOI: 10.1016/j.antiviral.2025.106279
Gilneia da Rosa , Paulo Henrique Hümmelgen Silva , José Valter Joaquim Silva Júnior , Micheli Mainardi Pillat , Bernardo Almeida Iglesias , Rudi Weiblen , Eduardo Furtado Flores
In this context, we evaluated the photodynamic effects of four cationic tetra-(pyridyl)porphyrins against Vaccinia virus Western Reserve (VACV WR) and Monkeypox virus (MPXV). The porphyrins were initially analyzed for cytotoxicity to Vero cells by MTT assay and the maximal non-cytotoxic concentrations were used in virucidal assays. For virucidal assays, VACV-WR (107.5 TCID50/mL) and MPXV suspensions (106.97 TCID50/mL) were incubated with porphyrins, exposed (or not) to white light conditions at 45 min. Aliquots of virus suspensions were collected and quantitated, comparing the titers with those of virus suspensions not exposed to porphyrins and/or to light. Porphyrins 4-PtTPyP, 3-H2TMeP and 4-H2TMeP exhibited light-dependent activity and completely inactivated VACV-WR and MPXV after 5, 30 and 45 min of light exposure, respectively. In contrast, derivative 3-PtTPyP inactivated the viruses even in the absence of white light exposure, a light-independent virucidal activity. Virucidal assays were performed in the presence/absence of ROS scavengers. Ascorbic acid (AA) was the only capable of completely inhibiting photodynamic inactivation by the three porphyrins. This indicates a type II photodynamic mechanism by singlet oxygen (1O2). These results demonstrated photodynamic inactivation of poxviruses by tetra-cationic porphyrins, supporting their potential use - especially 4-PtTPyP – for virus inactivation in many applications. These results also pave the way for testing porphyrin in PDT of poxvirus-induced cutaneous lesions. In addition, our data validated the use of VACV as a in vitro model for targeted MPXV virucidal testing.
{"title":"Remarkable photodynamic activity of tetra-cationic porphyrins against Vaccinia virus and Monkeypox virus","authors":"Gilneia da Rosa , Paulo Henrique Hümmelgen Silva , José Valter Joaquim Silva Júnior , Micheli Mainardi Pillat , Bernardo Almeida Iglesias , Rudi Weiblen , Eduardo Furtado Flores","doi":"10.1016/j.antiviral.2025.106279","DOIUrl":"10.1016/j.antiviral.2025.106279","url":null,"abstract":"<div><div>In this context, we evaluated the photodynamic effects of four cationic tetra-(pyridyl)porphyrins against Vaccinia virus Western Reserve (VACV WR) and Monkeypox virus (MPXV). The porphyrins were initially analyzed for cytotoxicity to Vero cells by MTT assay and the maximal non-cytotoxic concentrations were used in virucidal assays. For virucidal assays, VACV-WR (107.5 TCID50/mL) and MPXV suspensions (106.97 TCID50/mL) were incubated with porphyrins, exposed (or not) to white light conditions at 45 min. Aliquots of virus suspensions were collected and quantitated, comparing the titers with those of virus suspensions not exposed to porphyrins and/or to light. Porphyrins <strong>4-PtTPyP</strong>, <strong>3-H<sub>2</sub>TMeP</strong> and <strong>4-H<sub>2</sub>TMeP</strong> exhibited light-dependent activity and completely inactivated VACV-WR and MPXV after 5, 30 and 45 min of light exposure, respectively. In contrast, derivative 3-PtTPyP inactivated the viruses even in the absence of white light exposure, a light-independent virucidal activity. Virucidal assays were performed in the presence/absence of ROS scavengers. Ascorbic acid (AA) was the only capable of completely inhibiting photodynamic inactivation by the three porphyrins. This indicates a type II photodynamic mechanism by singlet oxygen (<sup>1</sup>O<sub>2</sub>). These results demonstrated photodynamic inactivation of poxviruses by tetra-cationic porphyrins, supporting their potential use - especially <strong>4-PtTPyP</strong> – for virus inactivation in many applications. These results also pave the way for testing porphyrin in PDT of poxvirus-induced cutaneous lesions. In addition, our data validated the use of VACV as a <em>in vitro</em> model for targeted MPXV virucidal testing.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"243 ","pages":"Article 106279"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145004674","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}
Pub Date : 2025-11-01Epub Date: 2025-09-03DOI: 10.1016/j.antiviral.2025.106271
Christian Gege, Thomas Hoffmann, Gerald Kleymann
The high incidence and prevalence of herpes infections pose a significant health burden worldwide. Herpes simplex virus infections are the cause of herpes labialis, genital herpes or herpes keratitis and in rare cases life-threatening herpes encephalitis, meningitis or disseminated disease. After primary infection, herpes simplex viruses (HSVes) establish latency in the trigeminal and sacral ganglia and at least 30 % of patients experience clinically manifestant recurrences for life. For effective treatment of these neurotrophic HSVes, adequate drug exposure in the nervous system is essential.
Here we report the post administration exposure of structurally different helicase-primase inhibitors (HPIs) in plasma, blood, organs and, in particular, the nervous system of animals by HPLC/MS. In diverse animal species, after single or multiple doses of helicase-primase drugs by oral or intravenous administration, only adibelivir (IM-250) achieved concentrations in the nervous system in the range of plasma or blood levels (ratio 0.5 to 4 nervous system/plasma), while other helicase-primase inhibitors with distinct structures, including amenamevir, pritelivir or ABI-5366, showed a low brain/plasma ratio of less than 0.1. The efficient passage of helicase-primase drugs through the blood-brain and blood-nerve barrier is based on their distinct structure and chemical properties. In preclinical studies published so far, adibelivir was efficacious in the herpes encephalitis and neonatal animal model and reduced the reactivation competence of the neuronal latent herpes viral reservoir. Ongoing clinical trials with HPIs will show whether sufficient drug exposure in brain and ganglia will translate into more effective herpes therapies for patients.
{"title":"Structural determinants of nervous system exposure of adibelivir (IM-250) and related herpes helicase-primase inhibitors across animal species","authors":"Christian Gege, Thomas Hoffmann, Gerald Kleymann","doi":"10.1016/j.antiviral.2025.106271","DOIUrl":"10.1016/j.antiviral.2025.106271","url":null,"abstract":"<div><div>The high incidence and prevalence of herpes infections pose a significant health burden worldwide. Herpes simplex virus infections are the cause of herpes labialis, genital herpes or herpes keratitis and in rare cases life-threatening herpes encephalitis, meningitis or disseminated disease. After primary infection, herpes simplex viruses (HSVes) establish latency in the trigeminal and sacral ganglia and at least 30 % of patients experience clinically manifestant recurrences for life. For effective treatment of these neurotrophic HSVes, adequate drug exposure in the nervous system is essential.</div><div>Here we report the post administration exposure of structurally different helicase-primase inhibitors (HPIs) in plasma, blood, organs and, in particular, the nervous system of animals by HPLC/MS. In diverse animal species, after single or multiple doses of helicase-primase drugs by oral or intravenous administration, only adibelivir (IM-250) achieved concentrations in the nervous system in the range of plasma or blood levels (ratio 0.5 to 4 nervous system/plasma), while other helicase-primase inhibitors with distinct structures, including amenamevir, pritelivir or ABI-5366, showed a low brain/plasma ratio of less than 0.1. The efficient passage of helicase-primase drugs through the blood-brain and blood-nerve barrier is based on their distinct structure and chemical properties. In preclinical studies published so far, adibelivir was efficacious in the herpes encephalitis and neonatal animal model and reduced the reactivation competence of the neuronal latent herpes viral reservoir. Ongoing clinical trials with HPIs will show whether sufficient drug exposure in brain and ganglia will translate into more effective herpes therapies for patients.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"243 ","pages":"Article 106271"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005816","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}
Pub Date : 2025-11-01Epub Date: 2025-09-13DOI: 10.1016/j.antiviral.2025.106282
John J. Suschak , Collin J. Fitzpatrick , Charles J. Shoemaker , Joshua D. Shamblin , Lauren E. White , Curtis R. Cline , Christina E. Douglas , Korey L. Delp , Trevor L.A. Burt , Kenise D. Lewis , Suma Ravulapalli , Susan Coyne , Carmen Ledesma-Feliciano , Gregg Wilson , Sarah L.W. Norris , Jennifer L. Scruggs , Ian Davis , Keersten M. Ricks , Christopher P. Stefan , Scott P. Olshner , Aura R. Garrison
Crimean-Congo hemorrhagic fever virus (CCHFV), a member of the Nairoviridae family, is the most widely distributed tick-borne virus of medical importance. There are no internationally licensed vaccines, and treatment is limited to supportive care. We previously developed a DNA vaccine expressing the full-length codon-optimized M-segment (CCHFV-MAfg09), encoding the structural and non-structural viral glycoproteins that protects mice against CCHFV when delivered by intramuscular electroporation (IM-EP). Here, the immunogenicity and protective efficacy of the vaccine delivered by IM-EP was assessed in the non-lethal CCHFV cynomolgus macaque model. The vaccine elicited a significant antibody response to two glycoproteins, the structural GC and non-structural GP38. CCHFV-MAfg09 elicited quantifiable T-cell responses directed against the glycoproteins encoded within the M-segment, with anti-GN immunity reaching significance. Upon intravenous infection with CCHFV, the vaccine protected 5/6 animals against viremia and reduced the pro-inflammatory response compared to sham vaccinated macaques. Numerous macaques also had detectable viral protein and viral RNA in several tissues 28 days post infection. In addition, we determined that an alternative delivery modality, jet injection, was immunogenic in both rabbits and mice, and conferred significant protection in mice. The simplicity and efficacy of disposable syringe needle-free injection system (NFIS) provides a pragmatic approach to advance the CCHF-M DNA vaccine into the clinic. Our M-segment based DNA vaccine elicits both cellular and humoral immunity and significant protection in mice and NHPs, demonstrating for the first time that a vaccine based on the glycoproteins alone is efficacious in the NHP model, which has not previously been shown.
{"title":"CCHFV-M based DNA vaccine is highly immunogenic in multiple species and protects against challenge in cynomolgus macaques","authors":"John J. Suschak , Collin J. Fitzpatrick , Charles J. Shoemaker , Joshua D. Shamblin , Lauren E. White , Curtis R. Cline , Christina E. Douglas , Korey L. Delp , Trevor L.A. Burt , Kenise D. Lewis , Suma Ravulapalli , Susan Coyne , Carmen Ledesma-Feliciano , Gregg Wilson , Sarah L.W. Norris , Jennifer L. Scruggs , Ian Davis , Keersten M. Ricks , Christopher P. Stefan , Scott P. Olshner , Aura R. Garrison","doi":"10.1016/j.antiviral.2025.106282","DOIUrl":"10.1016/j.antiviral.2025.106282","url":null,"abstract":"<div><div>Crimean-Congo hemorrhagic fever virus (CCHFV), a member of the <em>Nairoviridae</em> family, is the most widely distributed tick-borne virus of medical importance. There are no internationally licensed vaccines, and treatment is limited to supportive care. We previously developed a DNA vaccine expressing the full-length codon-optimized M-segment (CCHFV-M<sub>Afg09</sub>), encoding the structural and non-structural viral glycoproteins that protects mice against CCHFV when delivered by intramuscular electroporation (IM-EP). Here, the immunogenicity and protective efficacy of the vaccine delivered by IM-EP was assessed in the non-lethal CCHFV cynomolgus macaque model. The vaccine elicited a significant antibody response to two glycoproteins, the structural G<sub>C</sub> and non-structural GP38. CCHFV-M<sub>Afg09</sub> elicited quantifiable T-cell responses directed against the glycoproteins encoded within the M-segment, with anti-G<sub>N</sub> immunity reaching significance. Upon intravenous infection with CCHFV, the vaccine protected 5/6 animals against viremia and reduced the pro-inflammatory response compared to sham vaccinated macaques. Numerous macaques also had detectable viral protein and viral RNA in several tissues 28 days post infection. In addition, we determined that an alternative delivery modality, jet injection, was immunogenic in both rabbits and mice, and conferred significant protection in mice. The simplicity and efficacy of disposable syringe needle-free injection system (NFIS) provides a pragmatic approach to advance the CCHF-M DNA vaccine into the clinic. Our M-segment based DNA vaccine elicits both cellular and humoral immunity and significant protection in mice and NHPs, demonstrating for the first time that a vaccine based on the glycoproteins alone is efficacious in the NHP model, which has not previously been shown.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"243 ","pages":"Article 106282"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063302","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}
Pub Date : 2025-11-01Epub Date: 2025-08-30DOI: 10.1016/j.antiviral.2025.106267
Gede Ngurah Rsi Suwardana , Takayuki Abe , Lin Deng , Chieko Matsui , Takashi Okitsu , Takeshi Yamada , Manabu Hatano , Pattama Wiriyasermkul , Shushi Nagamori , Sameh A. Gad , Hussein H. Aly , Hironori Nishitsuji , Kunitada Shimotohno , Ikuo Shoji
Hepatitis B virus (HBV) infection is a major global health burden worldwide despite the availability of an effective vaccine and effective anti-HBV drugs. The currently approved anti-HBV drugs—i.e., nucleos(t)ide analogues and pegylated interferon α—can effectively suppress HBV replication, but rarely achieve a functional cure. Accordingly, new anti-HBV agents targeting different aspects of the HBV life cycle are needed. In this study, we screened for anti-HBV agents using the recombinant HBV expressing NanoLuc (NL) reporter gene (HBV/NL) and our original synthetic heterocyclic compound library. As a result, we identified a synthetic bile acid derivative, SO-145, as a potential novel anti-HBV agent, and investigated its effects in several cellular models of HBV. Treatment of HepG2-NTCP-C4 cells with SO-145 suppressed their NL activity following infection with HBV/NL. SO-145 suppressed HBV replication in PXB-cells infected with HBV genotype D, but did not show any inhibitory effect on HBV replication in Hep38.7-Tet cells. These results suggest that SO-145 specifically inhibits the early phase of the HBV life cycle. In other experiments, SO-145 was also shown to inhibit hepatitis D virus infection. Immunofluorescence analysis using fluorescent-labeled preS1 peptide revealed that SO-145 does not inhibit the preS1 attachment to the NTCP, but does markedly inhibit the HBV/preS1 internalization. Moreover, SO-145 does not inhibit the bile acid uptake facilitated by NTCP. Further mechanistic analysis suggested that SO-145 interferes with the NTCP oligomerization. Taken together, these results suggest that SO-145 inhibits HBV entry into hepatocytes by interfering with the NTCP oligomerization.
{"title":"A novel synthetic bile acid derivative inhibits hepatitis B virus infection at entry step by interfering with the oligomerization of sodium taurocholate co-transporting polypeptide","authors":"Gede Ngurah Rsi Suwardana , Takayuki Abe , Lin Deng , Chieko Matsui , Takashi Okitsu , Takeshi Yamada , Manabu Hatano , Pattama Wiriyasermkul , Shushi Nagamori , Sameh A. Gad , Hussein H. Aly , Hironori Nishitsuji , Kunitada Shimotohno , Ikuo Shoji","doi":"10.1016/j.antiviral.2025.106267","DOIUrl":"10.1016/j.antiviral.2025.106267","url":null,"abstract":"<div><div>Hepatitis B virus (HBV) infection is a major global health burden worldwide despite the availability of an effective vaccine and effective anti-HBV drugs. The currently approved anti-HBV drugs—i.e., nucleos(t)ide analogues and pegylated interferon α—can effectively suppress HBV replication, but rarely achieve a functional cure. Accordingly, new anti-HBV agents targeting different aspects of the HBV life cycle are needed. In this study, we screened for anti-HBV agents using the recombinant HBV expressing NanoLuc (NL) reporter gene (HBV/NL) and our original synthetic heterocyclic compound library. As a result, we identified a synthetic bile acid derivative, SO-145, as a potential novel anti-HBV agent, and investigated its effects in several cellular models of HBV. Treatment of HepG2-NTCP-C4 cells with SO-145 suppressed their NL activity following infection with HBV/NL. SO-145 suppressed HBV replication in PXB-cells infected with HBV genotype D, but did not show any inhibitory effect on HBV replication in Hep38.7-Tet cells. These results suggest that SO-145 specifically inhibits the early phase of the HBV life cycle. In other experiments, SO-145 was also shown to inhibit hepatitis D virus infection. Immunofluorescence analysis using fluorescent-labeled preS1 peptide revealed that SO-145 does not inhibit the preS1 attachment to the NTCP, but does markedly inhibit the HBV/preS1 internalization. Moreover, SO-145 does not inhibit the bile acid uptake facilitated by NTCP. Further mechanistic analysis suggested that SO-145 interferes with the NTCP oligomerization. Taken together, these results suggest that SO-145 inhibits HBV entry into hepatocytes by interfering with the NTCP oligomerization.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"243 ","pages":"Article 106267"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144934150","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}
Pub Date : 2025-11-01Epub Date: 2025-09-11DOI: 10.1016/j.antiviral.2025.106283
Ángeles Álvarez-Ribelles , Sandra Fernández-Rodríguez , Irene Carrasco-Hernández , Ana Blas-García , Víctor Collado-Díaz , Juan V. Esplugues
Integrase strand transfer inhibitors (INSTIs) have been linked to early cardiovascular (CV) complications. Despite the underlying mechanisms remain unclear, a proinflammatory effect has been suggested. Given the role of adhesion molecules in mediating endothelial interactions with leukocytes and platelets during vascular inflammation and thrombosis, we compared the impact of four INSTIs—dolutegravir (DTG), bictegravir (BIC), raltegravir (RAL), and cabotegravir (CAB)—and the non-nucleoside reverse transcriptase inhibitor doravirine (DOR), which is not associated with excessive CV risk, on adhesion molecule expression. Human blood, platelet-rich plasma, and endothelial cells from umbilical veins of healthy donors were incubated with clinically relevant drug concentrations and the expression of leukocyte, endothelium and platelet adhesion molecules was assessed by flow cytometry. BIC and CAB selectively activated neutrophils and monocytes, as evidenced by increased Mac-1 expression and L-selectin shedding. DTG, BIC, and DOR enhanced ICAM-1 expression on endothelial cells, while DTG and BIC also up-regulated VCAM-1, P-selectin and E-selectin levels. Additionally, DTG and BIC potentiated ADP-induced P-selectin expression in platelets. Overall, BIC produced the most significant pro-inflammatory changes, activating leukocytes, endothelial cells, and platelets; DTG primarily targeted the endothelium and platelets; CAB and DOR specifically activated leukocytes and endothelium, respectively, and RAL had no detectable effect. Our findings reveal distinct immunomodulatory profiles among the different INSTIs in vitro, rather than a class-wide effect. Future studies in patients with HIV will be needed to confirm the proinflammatory effects of DTG, BIC and CAB and to explore their potential implications for CV risk.
{"title":"Differential effects of antiretroviral HIV integrase inhibitors on vascular cell adhesion molecules","authors":"Ángeles Álvarez-Ribelles , Sandra Fernández-Rodríguez , Irene Carrasco-Hernández , Ana Blas-García , Víctor Collado-Díaz , Juan V. Esplugues","doi":"10.1016/j.antiviral.2025.106283","DOIUrl":"10.1016/j.antiviral.2025.106283","url":null,"abstract":"<div><div>Integrase strand transfer inhibitors (INSTIs) have been linked to early cardiovascular (CV) complications. Despite the underlying mechanisms remain unclear, a proinflammatory effect has been suggested. Given the role of adhesion molecules in mediating endothelial interactions with leukocytes and platelets during vascular inflammation and thrombosis, we compared the impact of four INSTIs—dolutegravir (DTG), bictegravir (BIC), raltegravir (RAL), and cabotegravir (CAB)—and the non-nucleoside reverse transcriptase inhibitor doravirine (DOR), which is not associated with excessive CV risk, on adhesion molecule expression. Human blood, platelet-rich plasma, and endothelial cells from umbilical veins of healthy donors were incubated with clinically relevant drug concentrations and the expression of leukocyte, endothelium and platelet adhesion molecules was assessed by flow cytometry. BIC and CAB selectively activated neutrophils and monocytes, as evidenced by increased Mac-1 expression and L-selectin shedding. DTG, BIC, and DOR enhanced ICAM-1 expression on endothelial cells, while DTG and BIC also up-regulated VCAM-1, P-selectin and E-selectin levels. Additionally, DTG and BIC potentiated ADP-induced P-selectin expression in platelets. Overall, BIC produced the most significant pro-inflammatory changes, activating leukocytes, endothelial cells, and platelets; DTG primarily targeted the endothelium and platelets; CAB and DOR specifically activated leukocytes and endothelium, respectively, and RAL had no detectable effect. Our findings reveal distinct immunomodulatory profiles among the different INSTIs in vitro, rather than a class-wide effect. Future studies in patients with HIV will be needed to confirm the proinflammatory effects of DTG, BIC and CAB and to explore their potential implications for CV risk.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"243 ","pages":"Article 106283"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058282","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}
Pub Date : 2025-11-01Epub Date: 2025-09-02DOI: 10.1016/j.antiviral.2025.106268
Pooja Chugh , Subodh Soni , Nisha Ghanghas , Sachin Kumar , Hari Mohan
The Japanese encephalitis virus (JEV) remains a major cause of viral encephalitis in Asia, with significant morbidity and mortality. This review offers a comprehensive overview of the current landscape of JEV research, focusing on its genomic structure, protein composition, and global epidemiology. We highlight the complexity of JEV transmission and pathogenesis, examining the interplay of demographic factors and geographic spread. In particular, we assess the evolution of diagnostic methodologies from traditional molecular and serological techniques to emerging biosensor-based approaches, emphasizing advancements in sensitivity and rapidity. The application of CRISPR/Cas systems for JEV detection marks a promising frontier in molecular diagnostics. Additionally, we review the current status of JEV vaccines, discussing recent innovations in vaccine development aimed at enhancing immunogenicity and accessibility. Beyond prevention, a spectrum of antiviral strategies—including direct-acting antivirals, entry inhibitors, host-directed modulators, neuroprotective agents, and steroidal/synthetic compounds—has demonstrated potent in vitro and in vivo efficacy, targeting viral enzymes, structural proteins, and host pathways. This review underscores the critical role of advanced detection strategies and vaccines in controlling JEV, offering insights into ongoing efforts to mitigate its impact in endemic regions.
{"title":"Comprehensive insights into Japanese encephalitis virus: From molecular characterization to advanced detection and vaccine strategies","authors":"Pooja Chugh , Subodh Soni , Nisha Ghanghas , Sachin Kumar , Hari Mohan","doi":"10.1016/j.antiviral.2025.106268","DOIUrl":"10.1016/j.antiviral.2025.106268","url":null,"abstract":"<div><div>The <em>Japanese encephalitis</em> virus (JEV) remains a major cause of viral encephalitis in Asia, with significant morbidity and mortality. This review offers a comprehensive overview of the current landscape of JEV research, focusing on its genomic structure, protein composition, and global epidemiology. We highlight the complexity of JEV transmission and pathogenesis, examining the interplay of demographic factors and geographic spread. In particular, we assess the evolution of diagnostic methodologies from traditional molecular and serological techniques to emerging biosensor-based approaches, emphasizing advancements in sensitivity and rapidity. The application of CRISPR/Cas systems for JEV detection marks a promising frontier in molecular diagnostics. Additionally, we review the current status of JEV vaccines, discussing recent innovations in vaccine development aimed at enhancing immunogenicity and accessibility. Beyond prevention, a spectrum of antiviral strategies—including direct-acting antivirals, entry inhibitors, host-directed modulators, neuroprotective agents, and steroidal/synthetic compounds—has demonstrated potent in vitro and in vivo efficacy, targeting viral enzymes, structural proteins, and host pathways. This review underscores the critical role of advanced detection strategies and vaccines in controlling JEV, offering insights into ongoing efforts to mitigate its impact in endemic regions.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"243 ","pages":"Article 106268"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999578","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}
Pub Date : 2025-11-01Epub Date: 2025-09-03DOI: 10.1016/j.antiviral.2025.106269
Chenxi Zhu , Ziqiao Wang , Zhendong Pan , Xinjia Mai , Yiyun Chen , Wen Zhang , Ping Zhao , Hailin Tang , Rong Zhang , Dapeng Zhou
DMBT1 is a large scavenger receptor cysteine rich (SRCR) B protein that has been reported as a tumor suppressor gene and a co-receptor for HIV-1 infection. Here, we found DMBT1 is a major mucosal protein bound to SARS-CoV-2. Overexpression of DMBT1 in 293T cells may enhanced infection by SARS-CoV-2 in ACE2 dependent manner. Blocking experiments using overlapping peptide library of SRCR domain of DMBT1 showed that peptide 7 (CQGRVEVLYRGSWGTV), which contains bacteria-binding VEVLXXXXW motif, could inhibit SARS-CoV-2 infection. High concentration of peptide 7 can significantly inhibit the replication of SARS-CoV-2 in hamsters. Peptide 7 inhibits SARS-CoV-2 infection by aggregating the spike protein, thereby reducing its binding to and internalization by host cells. The cysteine residue at the N-terminus of peptide 7 is critical for dimerization and antiviral activity. These results indicate that DMBT1 can serve as a candidate target for the development of antiviral drugs.
{"title":"DMBT1 promotes SARS-CoV-2 infection and its SRCR-derived peptide inhibits SARS-CoV-2 infection","authors":"Chenxi Zhu , Ziqiao Wang , Zhendong Pan , Xinjia Mai , Yiyun Chen , Wen Zhang , Ping Zhao , Hailin Tang , Rong Zhang , Dapeng Zhou","doi":"10.1016/j.antiviral.2025.106269","DOIUrl":"10.1016/j.antiviral.2025.106269","url":null,"abstract":"<div><div>DMBT1 is a large scavenger receptor cysteine rich (SRCR) B protein that has been reported as a tumor suppressor gene and a co-receptor for HIV-1 infection. Here, we found DMBT1 is a major mucosal protein bound to SARS-CoV-2. Overexpression of DMBT1 in 293T cells may enhanced infection by SARS-CoV-2 in ACE2 dependent manner. Blocking experiments using overlapping peptide library of SRCR domain of DMBT1 showed that peptide 7 (CQGRVEVLYRGSWGTV), which contains bacteria-binding VEVLXXXXW motif, could inhibit SARS-CoV-2 infection. High concentration of peptide 7 can significantly inhibit the replication of SARS-CoV-2 in hamsters. Peptide 7 inhibits SARS-CoV-2 infection by aggregating the spike protein, thereby reducing its binding to and internalization by host cells. The cysteine residue at the N-terminus of peptide 7 is critical for dimerization and antiviral activity. These results indicate that DMBT1 can serve as a candidate target for the development of antiviral drugs.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"243 ","pages":"Article 106269"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005829","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}
Pub Date : 2025-11-01Epub Date: 2025-09-12DOI: 10.1016/j.antiviral.2025.106281
Carol A. Anderson , Stephanie V. Trefry , Michael D. Barrera , Niloufar Boghdeh , Sanskruthi Sreepangi , Lorreta Opoku , Maria F. Galarza , Amanda R. Bliss , Janard L. Bleach , Farhang Alem , Elsa Ronzier , Elaine S. Cerchin , Christina L. Gardner , Crystal W. Burke , Aarthi Narayanan
There is an unmet need for broadly effective therapeutic strategies to address the globally expanding health burden caused by vector-transmitted viruses. Protein-protein interactions involving host and viral proteins are key regulators of a productive viral infection and interruption of such interactions can exert broad-spectrum antiviral outcomes. Verteporfin (VP), a small molecule that is currently approved by the United States Food and Drug Administration (FDA) for the treatment of age-related macular degeneration and a known Yes-associated protein (YAP) inhibitor, was identified as a robust inhibitor of Venezuelan Equine Encephalitis Virus (VEEV) TC-83 strain from a protein-protein interaction inhibitor library. VP demonstrated a cell type independent reduction of viral load with inhibitory mechanism including reduction of nonstructural and structural protein levels. VP treatment also impacted its known target YAP, resulting in reduced expression of total and phosphorylated YAP in virus-infected cells. The in vivo assessment of VP in a lethal infection rodent model demonstrated early promise by increasing survival of infected animals, while also indicating the need for additional improvements in dosing strategy. Assessment of VP-mediated inhibition of other RNA viruses including Old- and New-world alphaviruses, a prototype flavivirus and bunyavirus demonstrated the potential of VP to function as a broad-spectrum inhibitor of vector-transmitted viruses.
{"title":"Verteporfin is a broad-spectrum inhibitor of arboviruses and influences viral and host-based events","authors":"Carol A. Anderson , Stephanie V. Trefry , Michael D. Barrera , Niloufar Boghdeh , Sanskruthi Sreepangi , Lorreta Opoku , Maria F. Galarza , Amanda R. Bliss , Janard L. Bleach , Farhang Alem , Elsa Ronzier , Elaine S. Cerchin , Christina L. Gardner , Crystal W. Burke , Aarthi Narayanan","doi":"10.1016/j.antiviral.2025.106281","DOIUrl":"10.1016/j.antiviral.2025.106281","url":null,"abstract":"<div><div>There is an unmet need for broadly effective therapeutic strategies to address the globally expanding health burden caused by vector-transmitted viruses. Protein-protein interactions involving host and viral proteins are key regulators of a productive viral infection and interruption of such interactions can exert broad-spectrum antiviral outcomes. Verteporfin (VP), a small molecule that is currently approved by the United States Food and Drug Administration (FDA) for the treatment of age-related macular degeneration and a known Yes-associated protein (YAP) inhibitor, was identified as a robust inhibitor of Venezuelan Equine Encephalitis Virus (VEEV) TC-83 strain from a protein-protein interaction inhibitor library. VP demonstrated a cell type independent reduction of viral load with inhibitory mechanism including reduction of nonstructural and structural protein levels. VP treatment also impacted its known target YAP, resulting in reduced expression of total and phosphorylated YAP in virus-infected cells. The <em>in vivo</em> assessment of VP in a lethal infection rodent model demonstrated early promise by increasing survival of infected animals, while also indicating the need for additional improvements in dosing strategy. Assessment of VP-mediated inhibition of other RNA viruses including Old- and New-world alphaviruses, a prototype flavivirus and bunyavirus demonstrated the potential of VP to function as a broad-spectrum inhibitor of vector-transmitted viruses.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"243 ","pages":"Article 106281"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063357","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}
Pub Date : 2025-11-01Epub Date: 2025-09-06DOI: 10.1016/j.antiviral.2025.106280
Shanhui Ren , Haotai Chen , Shasha Wang , Zaib Ur Rehman , Xiaolong Gao , Xue Yang , Xiangwei Wang , Xiangping Yin , Jianlin Han , Yuefeng Sun
Due to the lack of timely vaccine prevention and effective drug treatment, lumpy skin disease is increasingly becoming a global epidemic, including in China. There is an urgent need to explore the pathogenic mechanism of lumpy skin disease virus (LSDV) and develop practical therapeutic approaches. The present study provides concrete evidence for the simultaneous induction and activation of nuclear ATM-mediated double-strand break and ATR kinase-dependent single-strand break signaling cascades during LSDV replication in the cytoplasm. Specific drug-inhibitory experiments targeting ATM and ATR kinase activity have showed that LSDV activates the host deoxyribonucleic acid (DNA) damage response (DDR) to facilitate viral replication via ATM-Chk2 rather than the ATR-Chk1 signaling axis in vitro. Meanwhile, animal experiments corroborated the efficacy of an inhibitor drug targeting ATM kinase in decreasing the clinical symptoms of LSDV-infected cattle in vivo. These findings highlight how LSDV exploits the nuclear DDR pathway to enhance replication in the cytoplasmic viral factory, deepening our understanding of virus-host interactions and providing a new target for developing specific antiviral drugs and interventions.
{"title":"Targeting of the cellular ATM rather than ATR kinase exhibits therapeutic potential during the lumpy skin disease virus infection in vivo and in vitro","authors":"Shanhui Ren , Haotai Chen , Shasha Wang , Zaib Ur Rehman , Xiaolong Gao , Xue Yang , Xiangwei Wang , Xiangping Yin , Jianlin Han , Yuefeng Sun","doi":"10.1016/j.antiviral.2025.106280","DOIUrl":"10.1016/j.antiviral.2025.106280","url":null,"abstract":"<div><div>Due to the lack of timely vaccine prevention and effective drug treatment, lumpy skin disease is increasingly becoming a global epidemic, including in China. There is an urgent need to explore the pathogenic mechanism of lumpy skin disease virus (LSDV) and develop practical therapeutic approaches. The present study provides concrete evidence for the simultaneous induction and activation of nuclear ATM-mediated double-strand break and ATR kinase-dependent single-strand break signaling cascades during LSDV replication in the cytoplasm. Specific drug-inhibitory experiments targeting ATM and ATR kinase activity have showed that LSDV activates the host deoxyribonucleic acid (DNA) damage response (DDR) to facilitate viral replication via ATM-Chk2 rather than the ATR-Chk1 signaling axis <em>in vitro</em>. Meanwhile, animal experiments corroborated the efficacy of an inhibitor drug targeting ATM kinase in decreasing the clinical symptoms of LSDV-infected cattle <em>in vivo</em>. These findings highlight how LSDV exploits the nuclear DDR pathway to enhance replication in the cytoplasmic viral factory, deepening our understanding of virus-host interactions and providing a new target for developing specific antiviral drugs and interventions.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"243 ","pages":"Article 106280"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145020190","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}
Pub Date : 2025-10-01Epub Date: 2025-08-14DOI: 10.1016/j.antiviral.2025.106259
Sarah Mafi , Jean-Luc Poyet , Sophie Alain , Gaëtan Ligat , Sébastien Hantz
Human cytomegalovirus (HCMV) is a major cause of morbidity in immunocompromised patients and the leading viral cause of congenital infection. The toxicity and emergence of resistance associated with current antivirals underscore the need for alternative therapeutic strategies. The viral terminase complex (pUL56-pUL89-pUL51), essential for genome cleavage and packaging and without homologs in mammalian cells, represents a promising antiviral target. This study evaluated the antiviral potential of peptides targeting the pUL56–pUL89 interaction domain. Peptides derived from the minimal interaction domain between pUL56 and pUL89 (WF10: 671WMVVKYMGFF680) or an extended sequence (PD17: 668PSEWMVVKYMGFFNFSD684) were synthesized to interfere with this interaction. To optimize intracellular delivery, peptides were conjugated to a cell-penetrating peptide (CPP) derived from either the HIV-1 transactivator of transcription (TAT) or the Antennapedia homeodomain of Drosophila melanogaster (penetratin; PT). Peptide candidates- PT-WF10, TAT-WF10, and PT-PD17- were evaluated in cellular models for cytotoxicity, hemolysis, antiviral activity, and intracellular distribution. TAT-WF10 and PT-PD17 significantly reduced the cytopathic foci in HCMV-infected cells, with IC50 values of 58 μM and 39 μM, respectively. PT-WF10 lacked antiviral activity, induced significant cytotoxicity and hemolysis, and was mainly localized in the cytoplasm, with only minimal nuclear signal. TAT-WF10 showed cytoplasmic and nuclear distribution, no hemolysis, but induced long-term cytotoxicity from 40 μM. PT-PD17 exhibited cytoplasmic and nuclear distribution, with no significant cytotoxicity or hemolysis up to 80 μM. This study provides the first proof of concept that a peptide targeting the pUL56–pUL89 interaction domain can inhibit HCMV replication. PT-PD17 demonstrated antiviral activity, intracellular distribution, and a favorable safety profile.
{"title":"First evidence of efficacy of peptides targeting the pUL56-pUL89 interaction domain of the human cytomegalovirus terminase complex","authors":"Sarah Mafi , Jean-Luc Poyet , Sophie Alain , Gaëtan Ligat , Sébastien Hantz","doi":"10.1016/j.antiviral.2025.106259","DOIUrl":"10.1016/j.antiviral.2025.106259","url":null,"abstract":"<div><div>Human cytomegalovirus (HCMV) is a major cause of morbidity in immunocompromised patients and the leading viral cause of congenital infection. The toxicity and emergence of resistance associated with current antivirals underscore the need for alternative therapeutic strategies. The viral terminase complex (pUL56-pUL89-pUL51), essential for genome cleavage and packaging and without homologs in mammalian cells, represents a promising antiviral target. This study evaluated the antiviral potential of peptides targeting the pUL56–pUL89 interaction domain. Peptides derived from the minimal interaction domain between pUL56 and pUL89 (WF10: <sub>671</sub>WMVVKYMGFF<sub>680</sub>) or an extended sequence (PD17: <sub>668</sub>PSEWMVVKYMGFFNFSD<sub>684</sub>) were synthesized to interfere with this interaction. To optimize intracellular delivery, peptides were conjugated to a cell-penetrating peptide (CPP) derived from either the HIV-1 transactivator of transcription (TAT) or the Antennapedia homeodomain of <em>Drosophila melanogaster</em> (penetratin; PT). Peptide candidates- PT-WF10, TAT-WF10, and PT-PD17- were evaluated in cellular models for cytotoxicity, hemolysis, antiviral activity, and intracellular distribution. TAT-WF10 and PT-PD17 significantly reduced the cytopathic foci in HCMV-infected cells, with IC<sub>50</sub> values of 58 μM and 39 μM, respectively. PT-WF10 lacked antiviral activity, induced significant cytotoxicity and hemolysis, and was mainly localized in the cytoplasm, with only minimal nuclear signal. TAT-WF10 showed cytoplasmic and nuclear distribution, no hemolysis, but induced long-term cytotoxicity from 40 μM. PT-PD17 exhibited cytoplasmic and nuclear distribution, with no significant cytotoxicity or hemolysis up to 80 μM. This study provides the first proof of concept that a peptide targeting the pUL56–pUL89 interaction domain can inhibit HCMV replication. PT-PD17 demonstrated antiviral activity, intracellular distribution, and a favorable safety profile.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"242 ","pages":"Article 106259"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858766","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}
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