Special Issue "Antiviral Agents"

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: closed (30 November 2019).

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Catherine Adamson
E-Mail Website
Guest Editor
School of Biology, Biomedical Sciences Research Complex, University of St Andrews, St. Andrews, United Kingdom
Interests: virology; antivirals; innate immunity; virus–host interactions; virus assembly and maturation; viral proteases; human immunodeficiency viruses; human cytomegalovirus; respiratory viruses; emerging and re-emerging viruses

Special Issue Information

Dear colleague,

Antiviral agents are required for the treatment of viral diseases. Antivirals drugs have been successfully developed and used clinically for a limited number of important human viral diseases, notably, HIV, HCV/HBV, Herpes and influenza infections. These antiviral drugs primarily target a specific viral protein preventing a key step in viral replication, such as viral entry, genome replication, proteolytic processing and assembly/release. Despite the success of these antiviral drugs, issues of drug resistance and toxicity remain challenging. Research on a variety of novel viral targets is ongoing to identify new mechanistic drug classes. Antiviral agents are not available against hundreds of viruses that cause disease in humans; in particular, the development of antiviral agents against emerging and re-emerging viruses is an increasing priority. In addition, traditional drug discovery approaches and strategies targeting host cell factors to develop broadly acting antivirals and combat drug resistance are being explored. Antiviral agents include conventional small molecules and novel agents such as therapeutic antibodies and nucleic acid-based therapies. In this Special Issue, we will focus on existing antiviral agents and related drug resistance, novel viral and host cell targets, new antiviral agents and innovations in drug discovery.

Dr. Catherine Adamson
Guest Editor

Manuscript Submission Information

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Keywords

  • antiviral drugs
  • broadly acting antivirals
  • therapeutic antibodies
  • nucleic acid-based therapies
  • drug resistance
  • drug discovery
  • HIV
  • HCV
  • influenza
  • herpes viruses
  • emerging and re-emerging viruses

Published Papers (22 papers)

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Editorial

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Editorial
Antiviral Agents: Discovery to Resistance
Viruses 2020, 12(4), 406; https://0-doi-org.brum.beds.ac.uk/10.3390/v12040406 - 07 Apr 2020
Cited by 3 | Viewed by 1989
Abstract
In the midst of the SARS-CoV-2/Covid-19 outbreak the need for research into, and development of, antiviral agents is brought into sharp focus worldwide for scientists, governments and the public alike [...] Full article
(This article belongs to the Special Issue Antiviral Agents)

Research

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Article
An Oleanolic Acid Derivative Inhibits Hemagglutinin-Mediated Entry of Influenza A Virus
Viruses 2020, 12(2), 225; https://0-doi-org.brum.beds.ac.uk/10.3390/v12020225 - 18 Feb 2020
Cited by 6 | Viewed by 1464
Abstract
Influenza A viruses (IAV) have been a major public health threat worldwide, and options for antiviral therapy become increasingly limited with the emergence of drug-resisting virus strains. New and effective anti-IAV drugs, especially for highly pathogenic influenza, with different modes of action, are [...] Read more.
Influenza A viruses (IAV) have been a major public health threat worldwide, and options for antiviral therapy become increasingly limited with the emergence of drug-resisting virus strains. New and effective anti-IAV drugs, especially for highly pathogenic influenza, with different modes of action, are urgently needed. The influenza virus glycoprotein hemagglutinin (HA) plays critical roles in the early stage of virus infection, including receptor binding and membrane fusion, making it a potential target for the development of anti-influenza drugs. In this study, we show that OA-10, a newly synthesized triterpene out of 11 oleanane-type derivatives, exhibited significant antiviral activity against four different subtypes of IAV (H1N1, H5N1, H9N2 and H3N2) replications in A549 cell cultures with EC50 ranging from 6.7 to 19.6 μM and a negligible cytotoxicity (CC50 > 640 μM). It inhibited acid-induced hemolysis in a dose-dependent manner, with an IC50 of 26 µM, and had a weak inhibition on the adsorption of H5 HA to chicken erythrocytes at higher concentrations (≥40 µM). Surface plasmon resonance (SPR) analysis showed that OA-10 interacted with HA in a dose-dependent manner with the equilibrium dissociation constants (KD) of the interaction of 2.98 × 10−12 M. Computer-aided molecular docking analysis suggested that OA-10 might bind to the cavity in HA stem region which is known to undergo significant rearrangement during membrane fusion. Our results demonstrate that OA-10 inhibits H5N1 IAV replication mainly by blocking the conformational changes of HA2 subunit required for virus fusion with endosomal membrane. These findings suggest that OA-10 could serve as a lead for further development of novel virus entry inhibitors to prevent and treat IAV infections. Full article
(This article belongs to the Special Issue Antiviral Agents)
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Article
An Engineered Microvirin Variant with Identical Structural Domains Potently Inhibits Human Immunodeficiency Virus and Hepatitis C Virus Cellular Entry
Viruses 2020, 12(2), 199; https://0-doi-org.brum.beds.ac.uk/10.3390/v12020199 - 11 Feb 2020
Cited by 3 | Viewed by 1150
Abstract
Microvirin (MVN) is one of the human immunodeficiency virus (HIV-1) entry inhibitor lectins, which consists of two structural domains sharing 35% sequence identity and contrary to many other antiviral lectins, it exists as a monomer. In this study, we engineered an MVN variant, [...] Read more.
Microvirin (MVN) is one of the human immunodeficiency virus (HIV-1) entry inhibitor lectins, which consists of two structural domains sharing 35% sequence identity and contrary to many other antiviral lectins, it exists as a monomer. In this study, we engineered an MVN variant, LUMS1, consisting of two domains with 100% sequence identity, thereby reducing the chemical heterogeneity, which is a major factor in eliciting immunogenicity. We determined carbohydrate binding of LUMS1 through NMR chemical shift perturbation and tested its anti-HIV activity in single-round infectivity assay and its anti-hepatitis C virus (HCV) activity in three different assays including HCVcc, HCVpp, and replicon assays. We further investigated the effect of LUMS1 on the activation of T helper (Th) and B cells through flow cytometry. LUMS1 showed binding to α(1-2)mannobiose, the minimum glycan epitope of MVN, potently inhibited HIV-1 and HCV with EC50 of 37.2 and 45.3 nM, respectively, and showed negligible cytotoxicity with CC50 > 10 µM against PBMCs, Huh-7.5 and HepG2 cells, and 4.9 µM against TZM-bl cells. LUMS1 did not activate Th cells, and its stimulatory effect on B cells was markedly less as compared to MVN. Together, with these effects, LUMS1 represents a potential candidate for the development of antiviral therapies. Full article
(This article belongs to the Special Issue Antiviral Agents)
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Article
Antiviral Effect of Epigallocatechin Gallate via Impairing Porcine Circovirus Type 2 Attachment to Host Cell Receptor
Viruses 2020, 12(2), 176; https://0-doi-org.brum.beds.ac.uk/10.3390/v12020176 - 04 Feb 2020
Cited by 13 | Viewed by 1240
Abstract
The green tea catechin epigallocatechin gallate (EGCG) exhibits antiviral activity against various viruses. Whether EGCG also inhibits the infectivity of circovirus remains unclear. In this study, we demonstrated the antiviral effect of EGCG on porcine circovirus type 2 (PCV2). EGCG targets PCV2 virions [...] Read more.
The green tea catechin epigallocatechin gallate (EGCG) exhibits antiviral activity against various viruses. Whether EGCG also inhibits the infectivity of circovirus remains unclear. In this study, we demonstrated the antiviral effect of EGCG on porcine circovirus type 2 (PCV2). EGCG targets PCV2 virions directly and blocks the attachment of virions to host cells. The microscale thermophoresis assay showed EGCG could interact with PCV2 capsid protein in vitro with considerable affinity (Kd = 98.03 ± 4.76 μM), thereby interfering with the binding of the capsid to the cell surface receptor heparan sulfate. The molecular docking analysis of capsid–EGCG interaction identified the key amino acids which formed the binding pocket accommodating EGCG. Amino acids ARG51, ASP70, ARG73 and ASP78 of capsid were found to be critical for maintaining the binding, and the arginine residues were also essential for the electrostatic interaction with heparan sulfate. The rescued mutant viruses also confirm the importance of the key amino acids of the capsid to the antiviral effect of EGCG. Our findings suggest that catechins could act as anti-infective agents against circovirus invasion, as well as provide the basic information for the development and synthesis of structure-based anti-circovirus drugs. Full article
(This article belongs to the Special Issue Antiviral Agents)
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Communication
5,6-Dichloro-2-Phenyl-Benzotriazoles: New Potent Inhibitors of Orthohantavirus
Viruses 2020, 12(1), 122; https://0-doi-org.brum.beds.ac.uk/10.3390/v12010122 - 20 Jan 2020
Cited by 8 | Viewed by 2139
Abstract
Orthohantaviruses, previously known as hantaviruses (family Hantaviridae, order Bunyavirales), are emerging zoonoses hosted by different rodent and insectivore species. Orthohantaviruses are transmitted by aerosolized excreta (urine, saliva and feces) of their reservoir hosts. When transmitted to humans, they cause hemorrhagic fever with renal [...] Read more.
Orthohantaviruses, previously known as hantaviruses (family Hantaviridae, order Bunyavirales), are emerging zoonoses hosted by different rodent and insectivore species. Orthohantaviruses are transmitted by aerosolized excreta (urine, saliva and feces) of their reservoir hosts. When transmitted to humans, they cause hemorrhagic fever with renal syndrome (HFRS) in Asia and Europe and hantavirus (cardio) pulmonary syndrome (HPS) in the Americas. Clinical studies have shown that early treatments of HFRS patients with ribavirin (RBV) improve prognosis. Nevertheless, there is the need for urgent development of specific antiviral drugs. In the search for new RNA virus inhibitors, we recently identified a series of variously substituted 5,6-dichloro-1(2)-phenyl-1(2)H-benzo[d][1,2,3]triazole derivatives active against the human respiratory syncytial virus (HRSV). Interestingly, several 2-phenyl-benzotriazoles resulted in fairly potent inhibitors of the Hantaan virus in a chemiluminescence focus reduction assay (C-FRA) showing an EC50 = 4–5 µM, ten-fold more active than ribavirin. Currently, there are no FDA approved drugs for the treatment of orthohantavirus infections. Antiviral activities and cytotoxicity profiles suggest that 5,6-dichloro-1(2)-phenyl-1(2)H-benzo[d][1,2,3]triazoles could be promising candidates for further investigation as a potential treatment of hantaviral diseases. Full article
(This article belongs to the Special Issue Antiviral Agents)
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Article
Ginsenoside Rg1 Suppresses Type 2 PRRSV Infection via NF-κB Signaling Pathway In Vitro, and Provides Partial Protection against HP-PRRSV in Piglet
Viruses 2019, 11(11), 1045; https://0-doi-org.brum.beds.ac.uk/10.3390/v11111045 - 10 Nov 2019
Cited by 4 | Viewed by 1311
Abstract
Porcine reproductive and respiratory syndrome virus (PRRSV) is a huge threat to the modern pig industry, and current vaccine prevention strategies could not provide full protection against it. Therefore, exploring new anti-PRRSV strategies is urgently needed. Ginsenoside Rg1, derived from ginseng and notoginseng, [...] Read more.
Porcine reproductive and respiratory syndrome virus (PRRSV) is a huge threat to the modern pig industry, and current vaccine prevention strategies could not provide full protection against it. Therefore, exploring new anti-PRRSV strategies is urgently needed. Ginsenoside Rg1, derived from ginseng and notoginseng, is shown to exert anti-inflammatory, neuronal apoptosis-suppressing and anti-oxidant effects. Here we demonstrate Rg1-inhibited PRRSV infection both in Marc-145 cells and porcine alveolar macrophages (PAMs) in a dose-dependent manner. Rg1 treatment affected multiple steps of the PRRSV lifecycle, including virus attachment, replication and release at concentrations of 10 or 50 µM. Meanwhile, Rg1 exhibited broad inhibitory activities against Type 2 PRRSV, including highly pathogenic PRRSV (HP-PRRSV) XH-GD and JXA1, NADC-30-like strain HNLY and classical strain VR2332. Mechanistically, Rg1 reduced mRNA levels of the pro-inflammatory cytokines, including IL-1β, IL-8, IL-6 and TNF-α, and decreased NF-κB signaling activation triggered by PRRSV infection. Furthermore, 4-week old piglets intramuscularly treated with Rg1 after being challenged with the HP-PRRSV JXA1 strain display moderate lung injury, decreased viral load in serum and tissues, and an improved survival rate. Collectively, our study provides research basis and supportive clinical data for using Ginsenoside Rg1 in PRRSV therapies in swine. Full article
(This article belongs to the Special Issue Antiviral Agents)
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Article
Decanoyl-Arg-Val-Lys-Arg-Chloromethylketone: An Antiviral Compound That Acts against Flaviviruses through the Inhibition of Furin-Mediated prM Cleavage
Viruses 2019, 11(11), 1011; https://0-doi-org.brum.beds.ac.uk/10.3390/v11111011 - 31 Oct 2019
Cited by 15 | Viewed by 1551
Abstract
Flaviviruses, such as Zika virus (ZIKV), Japanese encephalitis virus (JEV), Dengue virus (DENV), and West Nile virus (WNV), are important arthropod-borne pathogens that present an immense global health problem. Their unpredictable disease severity, unusual clinical features, and severe neurological manifestations underscore an urgent [...] Read more.
Flaviviruses, such as Zika virus (ZIKV), Japanese encephalitis virus (JEV), Dengue virus (DENV), and West Nile virus (WNV), are important arthropod-borne pathogens that present an immense global health problem. Their unpredictable disease severity, unusual clinical features, and severe neurological manifestations underscore an urgent need for antiviral interventions. Furin, a host proprotein convertase, is a key contender in processing flavivirus prM protein to M protein, turning the inert virus to an infectious particle. For this reason, the current study was planned to evaluate the antiviral activity of decanoyl-Arg-Val-Lys-Arg-chloromethylketone, a specific furin inhibitor, against flaviviruses, including ZIKV and JEV. Analysis of viral proteins revealed a significant increase in the prM/E index of ZIKV or JEV in dec-RVKR-cmk-treated Vero cells compared to DMSO-treated control cells, indicating dec-RVKR-cmk inhibits prM cleavage. Plaque assay, qRT-PCR, and immunofluorescence assay revealed a strong antiviral activity of dec-RVKR-cmk against ZIKV and JEV in terms of the reduction in virus progeny titer and in viral RNA and protein production in both mammalian cells and mosquito cells. Time-of-drug addition assay revealed that the maximum reduction of virus titer was observed in post-infection treatment. Furthermore, our results showed that dec-RVKR-cmk exerts its inhibitory action on the virus release and next round infectivity but not on viral RNA replication. Taken together, our study highlights an interesting antiviral activity of dec-RVKR-cmk against flaviviruses. Full article
(This article belongs to the Special Issue Antiviral Agents)
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Article
Prevalence and Correlates of Pre-Treatment HIV Drug Resistance among HIV-Infected Children in Ethiopia
Viruses 2019, 11(9), 877; https://0-doi-org.brum.beds.ac.uk/10.3390/v11090877 - 19 Sep 2019
Cited by 4 | Viewed by 1517
Abstract
Pediatric human immunodeficiency virus (HIV) care in resource-limited settings remains a major challenge to achieving global HIV treatment and virologic suppression targets, in part because the administration of combination antiretroviral therapies (cART) is inherently complex in this population and because viral load and [...] Read more.
Pediatric human immunodeficiency virus (HIV) care in resource-limited settings remains a major challenge to achieving global HIV treatment and virologic suppression targets, in part because the administration of combination antiretroviral therapies (cART) is inherently complex in this population and because viral load and drug resistance genotyping are not routinely available in these settings. Children may also be at elevated risk of transmission of drug-resistant HIV as a result of suboptimal antiretroviral administration for prevention of mother-to-child transmission. We investigated the prevalence and the correlates of pretreatment HIV drug resistance (PDR) among HIV-infected, cART-naive children in Ethiopia. We observed an overall PDR rate of 14%, where all cases featured resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs): ~9% of participants harbored resistance solely to NNRTIs while ~5% harbored resistance to both NNRTIs and nucleoside reverse transcriptase inhibitors (NRTIs). No resistance to protease inhibitors was observed. No sociodemographic or clinical parameters were significantly associated with PDR, though limited statistical power is noted. The relatively high (14%) rate of NNRTI resistance in cART-naive children supports the use of non-NNRTI-based regimens in first-line pediatric treatment in Ethiopia and underscores the urgent need for access to additional antiretroviral classes in resource-limited settings. Full article
(This article belongs to the Special Issue Antiviral Agents)
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Article
The 40 kDa Linear Polyethylenimine Inhibits Porcine Reproductive and Respiratory Syndrome Virus Infection by Blocking Its Attachment to Permissive Cells
Viruses 2019, 11(9), 876; https://0-doi-org.brum.beds.ac.uk/10.3390/v11090876 - 19 Sep 2019
Cited by 6 | Viewed by 1527
Abstract
Porcine reproductive and respiratory syndrome (PRRS) is one of the most economically devastating infectious diseases in pigs worldwide. The causative agent is the PRRS virus (PRRSV). In this study, we explored polyethylenimine (PEI), a cationic polymer with different forms (linear or branched), to [...] Read more.
Porcine reproductive and respiratory syndrome (PRRS) is one of the most economically devastating infectious diseases in pigs worldwide. The causative agent is the PRRS virus (PRRSV). In this study, we explored polyethylenimine (PEI), a cationic polymer with different forms (linear or branched), to inhibit the replication of PRRSV. Our results demonstrate that the linear but not the 40 kDa branched PEI, or the 25 kDa linear PEI, were well tolerated in cultured cells and exhibited a broad-spectrum inhibition of heterogeneous PRRSV-2 isolates in both MARC-145 cells and primary porcine pulmonary alveolar macrophages (PAMs). Further analysis suggests that PEI could prevent the attachment of PRRSV virions to the susceptible cells. Notably, PEI had a minimal effect on PRRSV internalization in MARC-145 cells, whereas PEI promoted the internalization of PRRSV virions in PAMs, which suggests that these two types of cells might have different internalization processes of PRRSV virions. In conclusion, our data demonstrate that PEI could be used as a novel inhibitor against PRRSV. Full article
(This article belongs to the Special Issue Antiviral Agents)
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Article
Brevilin A, a Sesquiterpene Lactone, Inhibits the Replication of Influenza A Virus In Vitro and In Vivo
Viruses 2019, 11(9), 835; https://0-doi-org.brum.beds.ac.uk/10.3390/v11090835 - 08 Sep 2019
Cited by 7 | Viewed by 1799
Abstract
With the emergence of drug-resistant strains of influenza A viruses (IAV), new antivirals are needed to supplement the existing counter measures against IAV infection. We have previously shown that brevilin A, a sesquiterpene lactone isolated from C. minima, suppresses the infection of [...] Read more.
With the emergence of drug-resistant strains of influenza A viruses (IAV), new antivirals are needed to supplement the existing counter measures against IAV infection. We have previously shown that brevilin A, a sesquiterpene lactone isolated from C. minima, suppresses the infection of influenza A/PR/8/34 (H1N1) in vitro. Here, we further investigate the antiviral activity and mode of action of brevilin A against different IAV subtypes. Brevilin A inhibited the replication of influenza A H1N1, H3N2, and H9N2 viruses in vitro. The suppression effect of brevilin A was observed as early as 4–8 hours post infection (hpi). Furthermore, we determined that brevilin A inhibited viral replication in three aspects, including viral RNA (vRNA) synthesis, expression of viral mRNA, and protein encoded from the M and NS segments, and nuclear export of viral ribonucleoproteins (vRNPs). The anti-IAV activity of brevilin A was further confirmed in mice. A delayed time-to-death with 50% surviving up to 14 days post infection was obtained with brevilin A (at a dose of 25 mg/kg) treated animals compared to the control cohorts. Together, these results are encouraging for the exploration of sesquiterpene lactones with similar structure to brevilin A as potential anti-influenza therapies. Full article
(This article belongs to the Special Issue Antiviral Agents)
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Article
Anti-Respiratory Syncytial Virus Activity of Plantago asiatica and Clerodendrum trichotomum Extracts In Vitro and In Vivo
Viruses 2019, 11(7), 604; https://0-doi-org.brum.beds.ac.uk/10.3390/v11070604 - 03 Jul 2019
Cited by 7 | Viewed by 2356
Abstract
The herbs Plantago asiatica and Clerodendrum trichotomum have been commonly used for centuries in indigenous and folk medicine in tropical and subtropical regions of the world. In this study, we show that extracts from these herbs have antiviral effects against the respiratory syncytial [...] Read more.
The herbs Plantago asiatica and Clerodendrum trichotomum have been commonly used for centuries in indigenous and folk medicine in tropical and subtropical regions of the world. In this study, we show that extracts from these herbs have antiviral effects against the respiratory syncytial virus (RSV) in vitro cell cultures and an in vivo mouse model. Treatment of HEp2 cells and A549 cells with a non-cytotoxic concentration of Plantago asiatica or Clerodendrum trichotomum extract significantly reduced RSV replication, RSV-induced cell death, RSV gene transcription, RSV protein synthesis, and also blocked syncytia formation. Interestingly, oral inoculation with each herb extract significantly improved viral clearance in the lungs of BALB/c mice. Based on reported information and a high-performance liquid chromatography (HPLC) analysis, the phenolic glycoside acteoside was identified as an active chemical component of both herb extracts. An effective dose of acteoside exhibited similar antiviral effects as each herb extract against RSV in vitro and in vivo. Collectively, these results suggest that extracts of Plantago asiatica and Clerodendrum trichotomum could provide a potent natural source of an antiviral drug candidate against RSV infection. Full article
(This article belongs to the Special Issue Antiviral Agents)
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Article
Genistein Has Antiviral Activity against Herpes B Virus and Acts Synergistically with Antiviral Treatments to Reduce Effective Dose
Viruses 2019, 11(6), 499; https://0-doi-org.brum.beds.ac.uk/10.3390/v11060499 - 31 May 2019
Cited by 16 | Viewed by 1583
Abstract
Herpes B virus is a deadly zoonotic agent that can be transmitted to humans from the macaque monkey, an animal widely used in biomedical research. Currently, there is no cure for human B virus infection and treatments require a life-long daily regimen of [...] Read more.
Herpes B virus is a deadly zoonotic agent that can be transmitted to humans from the macaque monkey, an animal widely used in biomedical research. Currently, there is no cure for human B virus infection and treatments require a life-long daily regimen of antivirals, namely acyclovir and ganciclovir. Long-term antiviral treatments have been associated with significant debilitating side effects, thus, there is an ongoing search for alternative efficacious antiviral treatment. In this study, the antiviral activity of genistein was quantified against B virus in a primary cell culture model system. Genistein prevented plaque formation of B virus and reduced virus production with an IC50 value of 33 and 46 μM for human and macaque fibroblasts, respectively. Genistein did not interfere directly with viral entry, but instead targeted an event post-viral replication. Finally, we showed that genistein could be used at its IC50 concentration in conjunction with both acyclovir and ganciclovir to reduce their effective dose against B virus with a 93% and 99% reduction in IC50 values, respectively. The results presented here illuminate the therapeutic potential of genistein as an effective antiviral agent against B virus when used alone or in combination with current antiviral therapies. Full article
(This article belongs to the Special Issue Antiviral Agents)
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Article
Emergence of Fluoxetine-Resistant Variants during Treatment of Human Pancreatic Cell Cultures Persistently Infected with Coxsackievirus B4
Viruses 2019, 11(6), 486; https://0-doi-org.brum.beds.ac.uk/10.3390/v11060486 - 28 May 2019
Cited by 4 | Viewed by 1104
Abstract
This study reports the antiviral activity of the drug fluoxetine against some enteroviruses (EV). We had previously established a model of persistent coxsackievirus B4 (CVB4) infection in pancreatic cell cultures and demonstrated that fluoxetine could clear the virus from these cultures. We further [...] Read more.
This study reports the antiviral activity of the drug fluoxetine against some enteroviruses (EV). We had previously established a model of persistent coxsackievirus B4 (CVB4) infection in pancreatic cell cultures and demonstrated that fluoxetine could clear the virus from these cultures. We further report the emergence of resistant variants during the treatment with fluoxetine in this model. Four independent persistent CVB4 infections in Panc-1 cells were treated with fluoxetine. The resistance to fluoxetine was investigated in an acute infection model. The 2C region, the putative target of fluoxetine antiviral activity, was sequenced. However, Fluoxetine treatment failed to clear CVB4 in two persistent infections. The resistance to fluoxetine was later confirmed in HEp-2 cells. The decrease in viral titer was significantly lower when cells were inoculated with the virus obtained from persistently infected cultures treated with fluoxetine than those from susceptible mock-treated cultures (0.6 log TCID50/mL versus 4.2 log TCID50/mL, p < 0.0001). Some previously described mutations and additional ones within the 2C protein were found in the fluoxetine-resistant isolates. The model of persistent infection is an interesting tool for assessing the emergence of variants resistant to anti-EV molecules. The resistance of EV strains to fluoxetine and its mechanisms require further investigation. Full article
(This article belongs to the Special Issue Antiviral Agents)
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Article
Potential Application of TALENs against Murine Cytomegalovirus Latent Infections
Viruses 2019, 11(5), 414; https://0-doi-org.brum.beds.ac.uk/10.3390/v11050414 - 03 May 2019
Cited by 6 | Viewed by 1631
Abstract
Cytomegalovirus (CMV) infections are still a global health problem, because the latent viruses persist in humans and cause recurring diseases. Currently, there are no therapies for CMV latent infections and the therapies for active infections are limited by side effects and other problems. [...] Read more.
Cytomegalovirus (CMV) infections are still a global health problem, because the latent viruses persist in humans and cause recurring diseases. Currently, there are no therapies for CMV latent infections and the therapies for active infections are limited by side effects and other problems. It is impossible to eradicate latent viruses in animals. HCMV (human CMV) is specific to human diseases; however, it is difficult to study HCMV due to its host specificity and long life cycle. Fortunately, MCMV (murine CMV) provides an excellent animal model. Here, three specific pairs of transcription activator-like effector nuclease (TALEN) plasmids (MCMV1–2, 3–4, and 5–6) were constructed to target the MCMV M80/80.5 sequence in order to test their efficacy in blocking MCMV lytic replication in NIH3T3 cell culture. The preliminary data showed that TALEN plasmids demonstrate specific targeting and cleavage in the MCMV M80/80.5 sequence and effectively inhibit MCMV growth in cell culture when the plasmid transfection is prior to the viral infection. The most specific pairs of TALEN plasmids (MCMV3–4) were further used to confirm the negative regulation of latent MCMV replication and gene expression in Balb/c mice. The injection of specific TALEN plasmids caused significant inhibition in the copy number level of immediately early gene (ie-1) DNA in five organs of mice, when compared with the controls. The result demonstrated that TALENs potentially provide an effective strategy to remove latent MCMV in animals. Full article
(This article belongs to the Special Issue Antiviral Agents)
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Article
Activity of Selected Nucleoside Analogue ProTides against Zika Virus in Human Neural Stem Cells
Viruses 2019, 11(4), 365; https://0-doi-org.brum.beds.ac.uk/10.3390/v11040365 - 20 Apr 2019
Cited by 8 | Viewed by 3534
Abstract
Zika virus (ZIKV), an emerging flavivirus that causes neurodevelopmental impairment to fetuses and has been linked to Guillain-Barré syndrome continues to threaten global health due to the absence of targeted prophylaxis or treatment. Nucleoside analogues are good examples of efficient anti-viral inhibitors, and [...] Read more.
Zika virus (ZIKV), an emerging flavivirus that causes neurodevelopmental impairment to fetuses and has been linked to Guillain-Barré syndrome continues to threaten global health due to the absence of targeted prophylaxis or treatment. Nucleoside analogues are good examples of efficient anti-viral inhibitors, and prodrug strategies using phosphate masking groups (ProTides) have been employed to improve the bioavailability of ribonucleoside analogues. Here, we synthesized and tested a small library of 13 ProTides against ZIKV in human neural stem cells. Strong activity was observed for 2′-C-methyluridine and 2′-C-ethynyluridine ProTides with an aryloxyl phosphoramidate masking group. Substitution of a 2-(methylthio) ethyl phosphoramidate for the aryloxyl phosphoramidate ProTide group of 2′-C-methyluridine completely abolished antiviral activity of the compound. The aryloxyl phosphoramidate ProTide of 2′-C-methyluridine outperformed the hepatitis C virus (HCV) drug sofosbuvir in suppression of viral titers and protection from cytopathic effect, while the former compound’s triphosphate active metabolite was better incorporated by purified ZIKV NS5 polymerase over time. These findings suggest both a nucleobase and ProTide group bias for the anti-ZIKV activity of nucleoside analogue ProTides in a disease-relevant cell model. Full article
(This article belongs to the Special Issue Antiviral Agents)
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Review

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Review
Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function
Viruses 2020, 12(1), 110; https://0-doi-org.brum.beds.ac.uk/10.3390/v12010110 - 16 Jan 2020
Cited by 15 | Viewed by 1985
Abstract
The human cytomegalovirus (HCMV), one of eight human herpesviruses, establishes lifelong latent infections in most people worldwide. Primary or reactivated HCMV infections cause severe disease in immunosuppressed patients and congenital defects in children. There is no vaccine for HCMV, and the currently approved [...] Read more.
The human cytomegalovirus (HCMV), one of eight human herpesviruses, establishes lifelong latent infections in most people worldwide. Primary or reactivated HCMV infections cause severe disease in immunosuppressed patients and congenital defects in children. There is no vaccine for HCMV, and the currently approved antivirals come with major limitations. Most approved HCMV antivirals target late molecular processes in the viral replication cycle including DNA replication and packaging. “Bright and early” events in HCMV infection have not been exploited for systemic prevention or treatment of disease. Initiation of HCMV replication depends on transcription from the viral major immediate-early (IE) gene. Alternative transcripts produced from this gene give rise to the IE1 and IE2 families of viral proteins, which localize to the host cell nucleus. The IE1 and IE2 proteins are believed to control all subsequent early and late events in HCMV replication, including reactivation from latency, in part by antagonizing intrinsic and innate immune responses. Here we provide an update on the regulation of major IE gene expression and the functions of IE1 and IE2 proteins. We will relate this insight to experimental approaches that target IE gene expression or protein function via molecular gene silencing and editing or small chemical inhibitors. Full article
(This article belongs to the Special Issue Antiviral Agents)
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Review
Structural Fluidity of the Human Immunodeficiency Virus Rev Response Element
Viruses 2020, 12(1), 86; https://0-doi-org.brum.beds.ac.uk/10.3390/v12010086 - 11 Jan 2020
Cited by 6 | Viewed by 1246
Abstract
Nucleocytoplasmic transport of unspliced and partially spliced human immunodeficiency virus (HIV) RNA is mediated in part by the Rev response element (RRE), a ~350 nt cis-acting element located in the envelope coding region of the viral genome. Understanding the interaction of the RRE [...] Read more.
Nucleocytoplasmic transport of unspliced and partially spliced human immunodeficiency virus (HIV) RNA is mediated in part by the Rev response element (RRE), a ~350 nt cis-acting element located in the envelope coding region of the viral genome. Understanding the interaction of the RRE with the viral Rev protein, cellular co-factors, and its therapeutic potential has been the subject of almost three decades of structural studies, throughout which a recurring discussion theme has been RRE topology, i.e., whether it comprises 4 or 5 stem-loops (SLs) and whether this has biological significance. Moreover, while in vitro mutagenesis allows the construction of 4 SL and 5 SL RRE conformers and testing of their roles in cell culture, it has not been immediately clear if such findings can be translated to a clinical setting. Herein, we review several articles demonstrating remarkable flexibility of the HIV-1 and HIV-2 RREs following initial observations that HIV-1 resistance to trans-dominant Rev therapy was founded in structural rearrangement of its RRE. These observations can be extended not only to cell culture studies demonstrating a growth advantage for the 5 SL RRE conformer but also to evolution in RRE topology in patient isolates. Finally, RRE conformational flexibility provides a target for therapeutic intervention, and we describe high throughput screening approaches to exploit this property. Full article
(This article belongs to the Special Issue Antiviral Agents)
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Review
Antiviral Agents as Therapeutic Strategies Against Cytomegalovirus Infections
Viruses 2020, 12(1), 21; https://0-doi-org.brum.beds.ac.uk/10.3390/v12010021 - 23 Dec 2019
Cited by 14 | Viewed by 2372
Abstract
Cytomegalovirus (CMV) is a threat to human health in the world, particularly for immunologically weak patients. CMV may cause opportunistic infections, congenital infections and central nervous system infections. CMV infections are difficult to treat due to their specific life cycles, mutation, and latency [...] Read more.
Cytomegalovirus (CMV) is a threat to human health in the world, particularly for immunologically weak patients. CMV may cause opportunistic infections, congenital infections and central nervous system infections. CMV infections are difficult to treat due to their specific life cycles, mutation, and latency characteristic. Despite recent advances, current drugs used for treating active CMV infections are limited in their efficacy, and the eradication of latent infections is impossible. Current antiviral agents which target the UL54 DNA polymerase are restricted because of nephrotoxicity and viral resistance. CMV also cannot be prevented or eliminated with a vaccine. Fortunately, letermovir which targets the human CMV (HCMV) terminase complex has been recently approved to treat CMV infections in humans. The growing point is developing antiviral agents against both lytically and latently infected cells. The nucleic acid-based therapeutic approaches including the external guide sequences (EGSs)-RNase, the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and transcription activator-like effector nucleases (TALENs) are being explored to remove acute and/or latent CMV infections. HCMV vaccine is being developed for prophylaxis. Additionally, adoptive T cell therapy (ACT) has been experimentally used to combate drug-resistant and recurrent CMV in patients after cell and/or organ transplantation. Developing antiviral agents is promising in this area to obtain fruitful outcomes and to have a great impact on humans for the therapy of CMV infections. Full article
(This article belongs to the Special Issue Antiviral Agents)
Review
Measles Encephalitis: Towards New Therapeutics
Viruses 2019, 11(11), 1017; https://0-doi-org.brum.beds.ac.uk/10.3390/v11111017 - 02 Nov 2019
Cited by 17 | Viewed by 2000
Abstract
Measles remains a major cause of morbidity and mortality worldwide among vaccine preventable diseases. Recent decline in vaccination coverage resulted in re-emergence of measles outbreaks. Measles virus (MeV) infection causes an acute systemic disease, associated in certain cases with central nervous system (CNS) [...] Read more.
Measles remains a major cause of morbidity and mortality worldwide among vaccine preventable diseases. Recent decline in vaccination coverage resulted in re-emergence of measles outbreaks. Measles virus (MeV) infection causes an acute systemic disease, associated in certain cases with central nervous system (CNS) infection leading to lethal neurological disease. Early following MeV infection some patients develop acute post-infectious measles encephalitis (APME), which is not associated with direct infection of the brain. MeV can also infect the CNS and cause sub-acute sclerosing panencephalitis (SSPE) in immunocompetent people or measles inclusion-body encephalitis (MIBE) in immunocompromised patients. To date, cellular and molecular mechanisms governing CNS invasion are still poorly understood. Moreover, the known MeV entry receptors are not expressed in the CNS and how MeV enters and spreads in the brain is not fully understood. Different antiviral treatments have been tested and validated in vitro, ex vivo and in vivo, mainly in small animal models. Most treatments have high efficacy at preventing infection but their effectiveness after CNS manifestations remains to be evaluated. This review describes MeV neural infection and current most advanced therapeutic approaches potentially applicable to treat MeV CNS infection. Full article
(This article belongs to the Special Issue Antiviral Agents)
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Review
Sphingolipids as Potential Therapeutic Targets against Enveloped Human RNA Viruses
Viruses 2019, 11(10), 912; https://0-doi-org.brum.beds.ac.uk/10.3390/v11100912 - 01 Oct 2019
Cited by 11 | Viewed by 1964
Abstract
Several notable human diseases are caused by enveloped RNA viruses: Influenza, AIDS, hepatitis C, dengue hemorrhagic fever, microcephaly, and Guillain–Barré Syndrome. Being enveloped, the life cycle of this group of viruses is critically dependent on host lipid biosynthesis. Viral binding and entry involve [...] Read more.
Several notable human diseases are caused by enveloped RNA viruses: Influenza, AIDS, hepatitis C, dengue hemorrhagic fever, microcephaly, and Guillain–Barré Syndrome. Being enveloped, the life cycle of this group of viruses is critically dependent on host lipid biosynthesis. Viral binding and entry involve interactions between viral envelope glycoproteins and cellular receptors localized to lipid-rich regions of the plasma membrane. Subsequent infection by these viruses leads to reorganization of cellular membranes and lipid metabolism to support the production of new viral particles. Recent work has focused on defining the involvement of specific lipid classes in the entry, genome replication assembly, and viral particle formation of these viruses in hopes of identifying potential therapeutic targets for the treatment or prevention of disease. In this review, we will highlight the role of host sphingolipids in the lifecycle of several medically important enveloped RNA viruses. Full article
(This article belongs to the Special Issue Antiviral Agents)
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Review
Human Antimicrobial Peptides as Therapeutics for Viral Infections
Viruses 2019, 11(8), 704; https://0-doi-org.brum.beds.ac.uk/10.3390/v11080704 - 01 Aug 2019
Cited by 79 | Viewed by 3953
Abstract
Successful in vivo infection following pathogen entry requires the evasion and subversion of multiple immunological barriers. Antimicrobial peptides (AMPs) are one of the first immune pathways upregulated during infection by multiple pathogens, in multiple organs in vivo. In humans, there are many classes [...] Read more.
Successful in vivo infection following pathogen entry requires the evasion and subversion of multiple immunological barriers. Antimicrobial peptides (AMPs) are one of the first immune pathways upregulated during infection by multiple pathogens, in multiple organs in vivo. In humans, there are many classes of AMPs exhibiting broad antimicrobial activities, with defensins and the human cathelicidin LL-37 being the best studied examples. Whereas historically the efficacy and therapeutic potential of AMPs against bacterial infection has been the primary focus of research, recent studies have begun to elucidate the antiviral properties of AMPs as well as their role in regulation of inflammation and chemoattraction. AMPs as therapeutic tools seem especially promising against emerging infectious viral pathogens for which no approved vaccines or treatments are currently available, such as dengue virus (DENV) and Zika virus (ZIKV). In this review, we summarize recent studies elucidating the efficacy and diverse mechanisms of action of various classes of AMPs against multiple viral pathogens, as well as the potential use of human AMPs in novel antiviral therapeutic strategies. Full article
(This article belongs to the Special Issue Antiviral Agents)

Other

Brief Report
Inhibition of Epstein-Barr Virus Lytic Reactivation by the Atypical Antipsychotic Drug Clozapine
Viruses 2019, 11(5), 450; https://0-doi-org.brum.beds.ac.uk/10.3390/v11050450 - 17 May 2019
Cited by 11 | Viewed by 2007
Abstract
Epstein–Barr virus (EBV), a member of the Herpesviridae family, maintains a lifelong latent infection in human B cells. Switching from the latent to the lytic phase of its lifecycle allows the virus to replicate and spread. The viral lytic cycle is induced in [...] Read more.
Epstein–Barr virus (EBV), a member of the Herpesviridae family, maintains a lifelong latent infection in human B cells. Switching from the latent to the lytic phase of its lifecycle allows the virus to replicate and spread. The viral lytic cycle is induced in infected cultured cells by drugs such as sodium butyrate and azacytidine. Lytic reactivation can be inhibited by natural products and pharmaceuticals. The anticonvulsant drugs valproic acid and valpromide inhibit EBV in Burkitt lymphoma cells. Therefore, other drugs that treat neurological and psychological disorders were investigated for effects on EBV lytic reactivation. Clozapine, an atypical antipsychotic drug used to treat schizophrenia and bipolar disorder, was found to inhibit the reactivation of the EBV lytic cycle. Levels of the viral lytic genes BZLF1, BRLF1, and BMLF1 were decreased by treatment with clozapine in induced Burkitt lymphoma cells. The effects on viral gene expression were dependent on the dose of clozapine, yet cells were viable at an inhibitory concentration of clozapine. One metabolite of clozapine—desmethylclozapine—also inhibited EBV lytic reactivation, while another metabolite—clozapine-N-oxide—had no effect. These drugs may be used to study cellular pathways that control the viral lytic switch in order to develop treatments for diseases caused by EBV. Full article
(This article belongs to the Special Issue Antiviral Agents)
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