Pub Date : 2024-09-10DOI: 10.1016/j.antiviral.2024.106003
Maria Grazia Martina , Vincent Carlen , Sarah Van der Reysen , Elena Bianchi , Noemi Cabella , Emmanuele Crespan , Marco Radi , Valeria Cagno
Broad-spectrum antivirals can be extremely important for pandemic preparedness. Targeting host factors dispensable for the host but indispensable for the virus can result in high barrier to resistance and a large range of viruses targeted. PI4KB is a lipid kinase involved in the replication of several RNA viruses, but common inhibitors of this target are mainly active against members of the Picornaviridae family. Herein we describe the optimization of bithiazole PI4KB inhibitors as broad-spectrum antivirals (BSAs) active against different members of the Picornaviridae, Coronaviridae, Flaviviridae and Poxviridae families. Since some of these viruses are transmitted via respiratory route, the efficacy of one of the most promising compounds was evaluated in an airway model. The molecule showed complete viral inhibition and absence of toxicity. These results pave the road for the development of new BSAs.
{"title":"Bithiazole inhibitors of PI4KB show broad-spectrum antiviral activity against different viral families","authors":"Maria Grazia Martina , Vincent Carlen , Sarah Van der Reysen , Elena Bianchi , Noemi Cabella , Emmanuele Crespan , Marco Radi , Valeria Cagno","doi":"10.1016/j.antiviral.2024.106003","DOIUrl":"10.1016/j.antiviral.2024.106003","url":null,"abstract":"<div><p>Broad-spectrum antivirals can be extremely important for pandemic preparedness. Targeting host factors dispensable for the host but indispensable for the virus can result in high barrier to resistance and a large range of viruses targeted. PI4KB is a lipid kinase involved in the replication of several RNA viruses, but common inhibitors of this target are mainly active against members of the <em>Picornaviridae</em> family. Herein we describe the optimization of bithiazole PI4KB inhibitors as broad-spectrum antivirals (BSAs) active against different members of the <em>Picornaviridae</em>, <em>Coronaviridae</em>, <em>Flaviviridae</em> and <em>Poxviridae</em> families. Since some of these viruses are transmitted via respiratory route, the efficacy of one of the most promising compounds was evaluated in an airway model. The molecule showed complete viral inhibition and absence of toxicity. These results pave the road for the development of new BSAs.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 106003"},"PeriodicalIF":4.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0166354224002122/pdfft?md5=25a911d3e9f87dcf8a8f784e017ff140&pid=1-s2.0-S0166354224002122-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142232860","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}
Pub Date : 2024-09-05DOI: 10.1016/j.antiviral.2024.105995
Jérémie Prévost , Angela Sloan , Yvon Deschambault , Nikesh Tailor , Kevin Tierney , Kimberly Azaransky , Srinivas Kammanadiminti , Douglas Barker , Shantha Kodihalli , David Safronetz
While historically confined to endemic areas, Monkeypox virus (MPXV) infection has increasingly garnered international attention due to sporadic outbreaks in non-endemic countries in the last two decades and its potential for human-to-human transmission. In 2022, a multi-country outbreak of mpox disease was declared by the World Health Organization (WHO) and nearly 100 000 mpox cases have been reported since the beginning of this pandemic. The clade II variant of the virus appears to be responsible for the vast majority of these infections. While there are no antiviral drugs currently approved to treat mpox specifically, the use of tecovirimat (TPOXX®) and brincidofovir (Tembexa®) is recommended by the Centers for Disease Control and Prevention (CDC) for compassionate use in severe mpox cases, since both are FDA-approved for the treatment of the closely related smallpox disease. Given the emergence of multiple tecovirimat-resistant infections, we aimed to evaluate the treatment efficacy of brincidofovir and its active compound, cidofovir, against MPXV clade II strains. Following intranasal infection, we show that cidofovir and brincidofovir can strongly reduce the viral replication of MPXV clade IIa and IIb viruses in the respiratory tract of susceptible mice when administered systemically and orally, respectively. The high antiviral activity of both compounds against historical and currently circulating MPXV strains supports their therapeutic potential for clinical application.
{"title":"Treatment efficacy of cidofovir and brincidofovir against clade II Monkeypox virus isolates","authors":"Jérémie Prévost , Angela Sloan , Yvon Deschambault , Nikesh Tailor , Kevin Tierney , Kimberly Azaransky , Srinivas Kammanadiminti , Douglas Barker , Shantha Kodihalli , David Safronetz","doi":"10.1016/j.antiviral.2024.105995","DOIUrl":"10.1016/j.antiviral.2024.105995","url":null,"abstract":"<div><p>While historically confined to endemic areas, Monkeypox virus (MPXV) infection has increasingly garnered international attention due to sporadic outbreaks in non-endemic countries in the last two decades and its potential for human-to-human transmission. In 2022, a multi-country outbreak of mpox disease was declared by the World Health Organization (WHO) and nearly 100 000 mpox cases have been reported since the beginning of this pandemic. The clade II variant of the virus appears to be responsible for the vast majority of these infections. While there are no antiviral drugs currently approved to treat mpox specifically, the use of tecovirimat (TPOXX®) and brincidofovir (Tembexa®) is recommended by the Centers for Disease Control and Prevention (CDC) for compassionate use in severe mpox cases, since both are FDA-approved for the treatment of the closely related smallpox disease. Given the emergence of multiple tecovirimat-resistant infections, we aimed to evaluate the treatment efficacy of brincidofovir and its active compound, cidofovir, against MPXV clade II strains. Following intranasal infection, we show that cidofovir and brincidofovir can strongly reduce the viral replication of MPXV clade IIa and IIb viruses in the respiratory tract of susceptible mice when administered systemically and orally, respectively. The high antiviral activity of both compounds against historical and currently circulating MPXV strains supports their therapeutic potential for clinical application.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 105995"},"PeriodicalIF":4.5,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0166354224002043/pdfft?md5=1e70e7d1d8050f2c5ebd4495a876d581&pid=1-s2.0-S0166354224002043-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142144924","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}
Pub Date : 2024-09-03DOI: 10.1016/j.antiviral.2024.105993
Martina Richter , Maria Khrenova , Elena Kazakova , Olga Riabova , Anna Egorova , Vadim Makarov , Michaela Schmidtke
Pyrazolo[3,4-d]pyrimidines represent one potent class of well tolerated and highly active rhinovirus (RV) inhibitors that act as capsid binders. The lead compound OBR-5-340 inhibits a broad-spectrum of RVs. Aiming to improve lead activity, we evaluated the impact of structural modifications in the 3-phenyl ring of OBR-5-340 on its potency and spectrum of anti-RV activity vitro. Our results demonstrate the crucial role of substitution at position 4 for strong, broad-spectrum anti-RV activity. The 4-methyl (RCB23137) and 4-chloro (RCB23138) derivatives outperformed OBR-5-340 in terms of potency and anti-RV activity spectrum. Based on these findings, the compounds were selected for computational binding studies. Molecular dynamic simulations with six RVs differing in OBR-5-340, RCB23137, and RCB23138 sensitivity proved the impact of dynamic features of two VP1 loops enveloping these inhibitors on antiviral potency.
{"title":"Dynamic features of virus protein 1 and substitutions in the 3-phenyl ring determine the potency and broad-spectrum activity of capsid-binding pyrazolo[3,4-d]pyrimidines against rhinoviruses","authors":"Martina Richter , Maria Khrenova , Elena Kazakova , Olga Riabova , Anna Egorova , Vadim Makarov , Michaela Schmidtke","doi":"10.1016/j.antiviral.2024.105993","DOIUrl":"10.1016/j.antiviral.2024.105993","url":null,"abstract":"<div><p>Pyrazolo[3,4-<em>d</em>]pyrimidines represent one potent class of well tolerated and highly active rhinovirus (RV) inhibitors that act as capsid binders. The lead compound OBR-5-340 inhibits a broad-spectrum of RVs. Aiming to improve lead activity, we evaluated the impact of structural modifications in the 3-phenyl ring of OBR-5-340 on its potency and spectrum of anti-RV activity <em>vitro</em>. Our results demonstrate the crucial role of substitution at position 4 for strong, broad-spectrum anti-RV activity. The 4-methyl (RCB23137) and 4-chloro (RCB23138) derivatives outperformed OBR-5-340 in terms of potency and anti-RV activity spectrum. Based on these findings, the compounds were selected for computational binding studies. Molecular dynamic simulations with six RVs differing in OBR-5-340, RCB23137, and RCB23138 sensitivity proved the impact of dynamic features of two VP1 loops enveloping these inhibitors on antiviral potency.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 105993"},"PeriodicalIF":4.5,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S016635422400202X/pdfft?md5=b1c2a35e05455c411efbb1f2c1d4fecc&pid=1-s2.0-S016635422400202X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131681","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}
Pub Date : 2024-09-03DOI: 10.1016/j.antiviral.2024.105994
Thuc Nguyen Dan Do , Rana Abdelnabi , Bernadett Boda , Samuel Constant , Johan Neyts , Dirk Jochmans
The use of fixed dose-combinations of antivirals with different mechanisms of action has proven key in the successful treatment of infections with HIV and HCV. For the treatment of infections with SARS-CoV-2 and possible future epi-/pandemic coronaviruses, it will be important to explore the efficacy of combinations of different drugs, in particular to avoid resistance development, such as in patients with immunodeficiencies. This work explores the effect of a combination of 3 broad-spectrum antiviral nucleosides on the replication of coronaviruses. To that end, we made use of primary human airway epithelial cell (HAEC) cultures grown at the air-liquid interface that were infected with the beta coronavirus OC43. We found that the triple combination of GS-441524 (the parent nucleoside of remdesivir), molnupiravir and ribavirin resulted in a more pronounced antiviral efficacy than what could be expected from a purely additive antiviral effect. The potency of this triple combination was next tested in SARS-CoV-2 infected hamsters in a prophylactic setup. To that end, for each of the drugs, intentionally suboptimal or even ineffective doses were selected. Yet, in the lungs of all hamsters that received triple prophylactic therapy (but not in those that received the respective double combinations) no infectious virus was detectable. Our findings indicate that co-administration of approved drugs for the treatment of coronavirus infections should be further explored but also against other families of viruses with epidemic and pandemic potential for which no effective antiviral treatment is available.
{"title":"The triple combination of Remdesivir (GS-441524), Molnupiravir and Ribavirin is highly efficient in inhibiting coronavirus replication in human nasal airway epithelial cell cultures and in a hamster infection model","authors":"Thuc Nguyen Dan Do , Rana Abdelnabi , Bernadett Boda , Samuel Constant , Johan Neyts , Dirk Jochmans","doi":"10.1016/j.antiviral.2024.105994","DOIUrl":"10.1016/j.antiviral.2024.105994","url":null,"abstract":"<div><p>The use of fixed dose-combinations of antivirals with different mechanisms of action has proven key in the successful treatment of infections with HIV and HCV. For the treatment of infections with SARS-CoV-2 and possible future epi-/pandemic coronaviruses, it will be important to explore the efficacy of combinations of different drugs, in particular to avoid resistance development, such as in patients with immunodeficiencies. This work explores the effect of a combination of 3 broad-spectrum antiviral nucleosides on the replication of coronaviruses. To that end, we made use of primary human airway epithelial cell (HAEC) cultures grown at the air-liquid interface that were infected with the beta coronavirus OC43. We found that the triple combination of GS-441524 (the parent nucleoside of remdesivir), molnupiravir and ribavirin resulted in a more pronounced antiviral efficacy than what could be expected from a purely additive antiviral effect. The potency of this triple combination was next tested in SARS-CoV-2 infected hamsters in a prophylactic setup. To that end, for each of the drugs, intentionally suboptimal or even ineffective doses were selected. Yet, in the lungs of all hamsters that received triple prophylactic therapy (but not in those that received the respective double combinations) no infectious virus was detectable. Our findings indicate that co-administration of approved drugs for the treatment of coronavirus infections should be further explored but also against other families of viruses with epidemic and pandemic potential for which no effective antiviral treatment is available.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 105994"},"PeriodicalIF":4.5,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0166354224002031/pdfft?md5=75eca4369d31dca76a301be203c81926&pid=1-s2.0-S0166354224002031-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139141","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}
Pub Date : 2024-08-23DOI: 10.1016/j.antiviral.2024.105991
Pureum Lee , Jihee Kim , Hanseul Oh , Chang-Ung Kim , Ahn Young Jeong , Moo-Seung Lee , Min Seong Jang , Jung Joo Hong , Jung-Eun Park , Doo-Jin Kim
Most coronavirus vaccines focus on the spike (S) antigen, but the frequent mutations in S raise concerns about the vaccine efficacy against new variants. Although additional antigens with conserved sequences are have been tested, the extent to which these vaccines can provide immunity against different coronavirus species remains unclear. In this study, we assessed the potential of nucleocapsid (N) as a coronavirus vaccine antigen. Immunization with MERS-CoV N induced robust immune responses, providing significant protection against MERS-CoV. Notably, MERS-CoV N elicited cross-reactive T cell responses to SARS-CoV-2 N and significantly reduced lung inflammation following a SARS-CoV-2 challenge in the transient hACE2 mouse model. However, in K18-hACE transgenic mice, the vaccine showed limited protection. Collectively, our findings suggest that coronavirus N can be an effective vaccine antigen against homologous viruses, but its efficacy may vary across different coronaviruses, highlighting the need for further research on pan-coronavirus vaccines using conserved antigens.
大多数冠状病毒疫苗都以尖峰(S)抗原为重点,但 S 抗原的频繁变异令人担忧疫苗对新变种的免疫效果。尽管已经对其他具有保守序列的抗原进行了测试,但这些疫苗能在多大程度上提供针对不同冠状病毒物种的免疫力仍不清楚。在本研究中,我们评估了核壳(N)作为冠状病毒疫苗抗原的潜力。用MERS-CoV N免疫可诱导强有力的免疫反应,提供针对MERS-CoV的显著保护。值得注意的是,在瞬时 hACE2 小鼠模型中,MERS-CoV N 可引起与 SARS-CoV-2 N 交叉反应的 T 细胞应答,并显著减轻 SARS-CoV-2 挑战后的肺部炎症。然而,在 K18-hACE 转基因小鼠中,疫苗显示出有限的保护作用。总之,我们的研究结果表明,冠状病毒 N 可以作为一种有效的疫苗抗原来对抗同源病毒,但其功效在不同的冠状病毒中可能会有所不同,这凸显了利用保守抗原进一步研究泛冠状病毒疫苗的必要性。
{"title":"Coronavirus nucleocapsid-based vaccine provides partial protection against hetero-species coronavirus in murine models","authors":"Pureum Lee , Jihee Kim , Hanseul Oh , Chang-Ung Kim , Ahn Young Jeong , Moo-Seung Lee , Min Seong Jang , Jung Joo Hong , Jung-Eun Park , Doo-Jin Kim","doi":"10.1016/j.antiviral.2024.105991","DOIUrl":"10.1016/j.antiviral.2024.105991","url":null,"abstract":"<div><p>Most coronavirus vaccines focus on the spike (S) antigen, but the frequent mutations in S raise concerns about the vaccine efficacy against new variants. Although additional antigens with conserved sequences are have been tested, the extent to which these vaccines can provide immunity against different coronavirus species remains unclear. In this study, we assessed the potential of nucleocapsid (N) as a coronavirus vaccine antigen. Immunization with MERS-CoV N induced robust immune responses, providing significant protection against MERS-CoV. Notably, MERS-CoV N elicited cross-reactive T cell responses to SARS-CoV-2 N and significantly reduced lung inflammation following a SARS-CoV-2 challenge in the transient hACE2 mouse model. However, in K18-hACE transgenic mice, the vaccine showed limited protection. Collectively, our findings suggest that coronavirus N can be an effective vaccine antigen against homologous viruses, but its efficacy may vary across different coronaviruses, highlighting the need for further research on pan-coronavirus vaccines using conserved antigens.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 105991"},"PeriodicalIF":4.5,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054774","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}
Given the worldwide risk for the outbreak of emerging/re-emerging respiratory viruses, establishment of new antiviral strategies is greatly demanded. In this study, we present a scheme to identify gapmer antisense oligonucleotides (ASOs) targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA that efficiently inhibit viral replication. We synthesized approximately 300 gapmer ASOs designed to target various SARS-CoV-2 RNA regions and evaluated their activity in cell-based assays. Through a multistep screening in cell culture systems, we identified that ASO#41, targeting the coding region for viral main protease, reduced SARS-CoV-2 RNA levels in infected cells and inhibited virus-induced cytopathic effects. Antiviral effect of ASO#41 was also observed in iPS cell-derived human lung organoids. ASO#41 depleted intracellular viral RNAs during genome replication in an endogenous RNaseH-dependent manner. ASO#41 showed a wide range of antiviral activity against SARS-CoV-2 variants of concern including Alpha, Delta, and Omicron. Intranasal administration to mice exhibited intracellular accumulation of ASO#41 in the lung and significantly reduced the viral infectious titer, with milder body weight loss due to SARS-CoV-2 infection. Further chemical modification with phosphoryl guanidine-containing backbone linkages provided an elevation of anti-SARS-CoV-2 activity, with 23.4 nM of 50% antiviral inhibitory concentration, one of the strongest anti-SARS-CoV-2 ASOs reported so far. Our study presents an approach to identify active ASOs against SARS-CoV-2, which is potentially useful for establishing an antiviral strategy by targeting genome RNA of respiratory viruses.
{"title":"Anti-SARS-CoV-2 gapmer antisense oligonucleotides targeting the main protease region of viral RNA","authors":"Masako Yamasaki , Wakana Saso , Takuya Yamamoto , Masayoshi Sato , Hiroko Takagi , Tetsuya Hasegawa , Yuji Kozakura , Hiroyuki Yokoi , Hirofumi Ohashi , Kana Tsuchimoto , Rina Hashimoto , Shuetsu Fukushi , Akihiko Uda , Masamichi Muramatsu , Kazuo Takayama , Ken Maeda , Yoshimasa Takahashi , Tsuyoshi Nagase , Koichi Watashi","doi":"10.1016/j.antiviral.2024.105992","DOIUrl":"10.1016/j.antiviral.2024.105992","url":null,"abstract":"<div><p>Given the worldwide risk for the outbreak of emerging/re-emerging respiratory viruses, establishment of new antiviral strategies is greatly demanded. In this study, we present a scheme to identify gapmer antisense oligonucleotides (ASOs) targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA that efficiently inhibit viral replication. We synthesized approximately 300 gapmer ASOs designed to target various SARS-CoV-2 RNA regions and evaluated their activity in cell-based assays. Through a multistep screening in cell culture systems, we identified that ASO#41, targeting the coding region for viral main protease, reduced SARS-CoV-2 RNA levels in infected cells and inhibited virus-induced cytopathic effects. Antiviral effect of ASO#41 was also observed in iPS cell-derived human lung organoids. ASO#41 depleted intracellular viral RNAs during genome replication in an endogenous RNaseH-dependent manner. ASO#41 showed a wide range of antiviral activity against SARS-CoV-2 variants of concern including Alpha, Delta, and Omicron. Intranasal administration to mice exhibited intracellular accumulation of ASO#41 in the lung and significantly reduced the viral infectious titer, with milder body weight loss due to SARS-CoV-2 infection. Further chemical modification with phosphoryl guanidine-containing backbone linkages provided an elevation of anti-SARS-CoV-2 activity, with 23.4 nM of 50% antiviral inhibitory concentration, one of the strongest anti-SARS-CoV-2 ASOs reported so far. Our study presents an approach to identify active ASOs against SARS-CoV-2, which is potentially useful for establishing an antiviral strategy by targeting genome RNA of respiratory viruses.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"230 ","pages":"Article 105992"},"PeriodicalIF":4.5,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054773","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 : 2024-08-21DOI: 10.1016/j.antiviral.2024.105989
Zsuzsa K. Szemere, Eain A. Murphy
Recently it was discovered that extracellular 2′-3′cGAMP can activate the STING pathway in a cGAS-independent fashion by being transported across the cell membrane via the folate transporter, SLC19A1, the first identified extracellular antiporter of this critical signaling molecule in cancer cells. We hypothesized that this non-canonical activation of STING pathway would function to establish an antiviral state similar to that seen with the paracrine antiviral activities of interferon. Herein, we report that treatment of the monocytic cell line, THP-1 cells and SH-SY5Y neuronal cell line with exogenous 2′-3′cGAMP induces interferon production and establishes an antiviral state that limits herpes simplex virus-1 (HSV-1), a ubiquitous virus with high seropositivity in the human population. Using either pharmaceutical inhibition or genetic knockout of SLC19A1 blocks the 2′-3′cGAMP-induced inhibition of viral replication. Our data indicate SLC19A1 functions as a newly identified antiviral mediator for extracellular 2′-3′cGAMP. This work presents novel and important findings about an antiviral mechanism which information could aid in the development of better antiviral drugs in the future.
{"title":"Import of extracellular 2′-3′cGAMP by the folate transporter, SLC19A1, establishes an antiviral response that limits herpes simplex virus-1","authors":"Zsuzsa K. Szemere, Eain A. Murphy","doi":"10.1016/j.antiviral.2024.105989","DOIUrl":"10.1016/j.antiviral.2024.105989","url":null,"abstract":"<div><p>Recently it was discovered that extracellular 2′-3′cGAMP can activate the STING pathway in a cGAS-independent fashion by being transported across the cell membrane via the folate transporter, SLC19A1, the first identified extracellular antiporter of this critical signaling molecule in cancer cells. We hypothesized that this non-canonical activation of STING pathway would function to establish an antiviral state similar to that seen with the paracrine antiviral activities of interferon. Herein, we report that treatment of the monocytic cell line, THP-1 cells and SH-SY5Y neuronal cell line with exogenous 2′-3′cGAMP induces interferon production and establishes an antiviral state that limits herpes simplex virus-1 (HSV-1), a ubiquitous virus with high seropositivity in the human population. Using either pharmaceutical inhibition or genetic knockout of SLC19A1 blocks the 2′-3′cGAMP-induced inhibition of viral replication. Our data indicate SLC19A1 functions as a newly identified antiviral mediator for extracellular 2′-3′cGAMP. This work presents novel and important findings about an antiviral mechanism which information could aid in the development of better antiviral drugs in the future.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"230 ","pages":"Article 105989"},"PeriodicalIF":4.5,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999370","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 : 2024-08-19DOI: 10.1016/j.antiviral.2024.105973
Veronica Martin , Beatriz Guerra , Bruno Hernaez , Sandrine Kappler-Gratias , Franck Gallardo , Milagros Guerra , German Andres , Ali Alejo
African swine fever virus (ASFV) infection causes a frequently fatal disease in domestic swine that has affected more than 50 countries worldwide since 2021, with a major impact on animal welfare and economy. The development of effective vaccines or antivirals against this disease are urgently required for its effective control. Live detection of viral replication has been used as a tool for the screening and characterization of antiviral compounds in other dsDNA genome containing viruses. Here, we have adapted the ANCHOR fluorescent DNA labelling system to ASFV by constructing and characterizing a novel recombinant virus. We show that this virus is viable and effectively tags viral DNA replication sites, which can be detected and quantified in real time. Further, we have used high content cell microscopy to test the antiviral activity of bisbenzimide compounds and show that Hoechst 33342 has specific anti-ASFV activity. We expect this novel tool to be useful both in the further study of ASFV replication as in the screening of new specific antiviral compounds.
{"title":"A novel live DNA tagging system for African swine fever virus shows that bisbenzimide Hoechst 33342 can effectively block its replication","authors":"Veronica Martin , Beatriz Guerra , Bruno Hernaez , Sandrine Kappler-Gratias , Franck Gallardo , Milagros Guerra , German Andres , Ali Alejo","doi":"10.1016/j.antiviral.2024.105973","DOIUrl":"10.1016/j.antiviral.2024.105973","url":null,"abstract":"<div><p>African swine fever virus (ASFV) infection causes a frequently fatal disease in domestic swine that has affected more than 50 countries worldwide since 2021, with a major impact on animal welfare and economy. The development of effective vaccines or antivirals against this disease are urgently required for its effective control. Live detection of viral replication has been used as a tool for the screening and characterization of antiviral compounds in other dsDNA genome containing viruses. Here, we have adapted the ANCHOR fluorescent DNA labelling system to ASFV by constructing and characterizing a novel recombinant virus. We show that this virus is viable and effectively tags viral DNA replication sites, which can be detected and quantified in real time. Further, we have used high content cell microscopy to test the antiviral activity of bisbenzimide compounds and show that Hoechst 33342 has specific anti-ASFV activity. We expect this novel tool to be useful both in the further study of ASFV replication as in the screening of new specific antiviral compounds.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"230 ","pages":"Article 105973"},"PeriodicalIF":4.5,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0166354224001827/pdfft?md5=40944046fc07cd5d2704ccfff7de584e&pid=1-s2.0-S0166354224001827-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142012686","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}
Pub Date : 2024-08-16DOI: 10.1016/j.antiviral.2024.105990
Michael O. Okpara , Frederick Weaver , Adrian Whitehouse , Clinton G.L. Veale , Adrienne L. Edkins
Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent for primary effusion lymphoma (PEL), multicentric Castleman's disease (MCD) and Kaposi's sarcoma (KS). KSHV is one of the oncoviruses that contribute to 1.5 million new infection-related cancer cases annually. Currently, there are no targeted therapies for KSHV-associated diseases. Through the development of a medium-throughput phenotype-based ELISA screening platform based on KSHV ORF57 protein detection, we screened the Medicines for Malaria Venture (MMV) Pandemic Response Box for non-cytotoxic inhibitors of KSHV lytic replication. MMV1645152 was identified as a promising inhibitor of KSHV lytic replication, suppressing KSHV immediate-early and late lytic gene expression and blocking the production of infectious KSHV virion particles at non-cytotoxic concentrations in cell line models of KSHV infection with or without EBV coinfection. MMV1645152 is a promising hit compound for the development of future therapeutic agents against KSHV-associated malignancies.
{"title":"Discovery of a small-molecule inhibitor of KSHV lytic replication from the MMV pandemic response box","authors":"Michael O. Okpara , Frederick Weaver , Adrian Whitehouse , Clinton G.L. Veale , Adrienne L. Edkins","doi":"10.1016/j.antiviral.2024.105990","DOIUrl":"10.1016/j.antiviral.2024.105990","url":null,"abstract":"<div><p>Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent for primary effusion lymphoma (PEL), multicentric Castleman's disease (MCD) and Kaposi's sarcoma (KS). KSHV is one of the oncoviruses that contribute to 1.5 million new infection-related cancer cases annually. Currently, there are no targeted therapies for KSHV-associated diseases. Through the development of a medium-throughput phenotype-based ELISA screening platform based on KSHV ORF57 protein detection, we screened the Medicines for Malaria Venture (MMV) Pandemic Response Box for non-cytotoxic inhibitors of KSHV lytic replication. MMV1645152 was identified as a promising inhibitor of KSHV lytic replication, suppressing KSHV immediate-early and late lytic gene expression and blocking the production of infectious KSHV virion particles at non-cytotoxic concentrations in cell line models of KSHV infection with or without EBV coinfection. MMV1645152 is a promising hit compound for the development of future therapeutic agents against KSHV-associated malignancies.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"230 ","pages":"Article 105990"},"PeriodicalIF":4.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0166354224001992/pdfft?md5=912944c9476720bdf0a61c3a23c9cb41&pid=1-s2.0-S0166354224001992-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999369","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}
Pub Date : 2024-08-16DOI: 10.1016/j.antiviral.2024.105988
Kaiming Tao, Jinru Zhou, Pavithra Nagarajan, Philip L. Tzou, Robert W. Shafer
Background
In vitro passage experiments are crucial to the development of antiretroviral (ARV) drugs.
Methods
We created an online database containing data from 102 published studies in which HIV-1 or HIV-2 was cultured with increasing concentrations of the FDA-approved nucleoside RT inhibitors (NRTIs), nonnucleoside RT inhibitors (NNRTIs), integrase strand transfer inhibitors (INSTIs), protease inhibitors (PIs), capsid inhibitor (CAI) lenacapavir, and nucleoside RT translocation inhibitor (NRTTI) islatravir. We summarized the mutations selected in the subset of passage experiments with NRTIs lamivudine (3TC), emtricitabine (FTC), abacavir (ABC), tenofovir (TFV), and zidovudine (AZT), NNRTIs doravirine (DOR), efavirenz (EFV), and rilpivirine (RPV), INSTIs bictegravir (BIC), cabotegravir (CAB), and dolutegravir (DTG), and PIs atazanavir (ATV), darunavir (DRV), and lopinavir (LPV). Mutations selected in vitro were compared with those selected in persons receiving the same ARV.
Results
Twenty-seven studies described 89 experiments of wildtype isolates passaged with 3TC, FTC, ABC, TFV, or AZT; sixteen studies described 89 experiments passaged with EFV, RPV, or DOR; eleven studies described 76 experiments passaged with the INSTIs BIC, CAB, or DTG; six studies described 33 experiments passaged with ATV, LPV, or DRV. With several exceptions, mutations selected in two or more experiments were among the most common mutations selected in persons receiving the same ARV.
Conclusions
We created a database of published ARV in vitro selection experiments. Mutations emerging from these experiments generally predict those observed in persons receiving the same ARV. However, there are notable differences in mutation frequencies between in vitro and in vivo settings.
{"title":"Comprehensive database of HIV mutations selected during antiretroviral in vitro passage experiments","authors":"Kaiming Tao, Jinru Zhou, Pavithra Nagarajan, Philip L. Tzou, Robert W. Shafer","doi":"10.1016/j.antiviral.2024.105988","DOIUrl":"10.1016/j.antiviral.2024.105988","url":null,"abstract":"<div><h3>Background</h3><p><em>In vitro</em> passage experiments are crucial to the development of antiretroviral (ARV) drugs.</p></div><div><h3>Methods</h3><p>We created an online database containing data from 102 published studies in which HIV-1 or HIV-2 was cultured with increasing concentrations of the FDA-approved nucleoside RT inhibitors (NRTIs), nonnucleoside RT inhibitors (NNRTIs), integrase strand transfer inhibitors (INSTIs), protease inhibitors (PIs), capsid inhibitor (CAI) lenacapavir, and nucleoside RT translocation inhibitor (NRTTI) islatravir. We summarized the mutations selected in the subset of passage experiments with NRTIs lamivudine (3TC), emtricitabine (FTC), abacavir (ABC), tenofovir (TFV), and zidovudine (AZT), NNRTIs doravirine (DOR), efavirenz (EFV), and rilpivirine (RPV), INSTIs bictegravir (BIC), cabotegravir (CAB), and dolutegravir (DTG), and PIs atazanavir (ATV), darunavir (DRV), and lopinavir (LPV). Mutations selected <em>in vitro</em> were compared with those selected in persons receiving the same ARV.</p></div><div><h3>Results</h3><p>Twenty-seven studies described 89 experiments of wildtype isolates passaged with 3TC, FTC, ABC, TFV, or AZT; sixteen studies described 89 experiments passaged with EFV, RPV, or DOR; eleven studies described 76 experiments passaged with the INSTIs BIC, CAB, or DTG; six studies described 33 experiments passaged with ATV, LPV, or DRV. With several exceptions, mutations selected in two or more experiments were among the most common mutations selected in persons receiving the same ARV.</p></div><div><h3>Conclusions</h3><p>We created a database of published ARV <em>in vitro</em> selection experiments. Mutations emerging from these experiments generally predict those observed in persons receiving the same ARV. However, there are notable differences in mutation frequencies between <em>in vitro</em> and <em>in vivo</em> settings.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"230 ","pages":"Article 105988"},"PeriodicalIF":4.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0166354224001979/pdfft?md5=0b3b2fe533646d47200e5fa992150e2d&pid=1-s2.0-S0166354224001979-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999368","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}