scholarly journals Ilaprazole and other novel prazole-based compounds that bind Tsg101 inhibit viral budding of HSV-1/2 and HIV from cells

2021 ◽  
Author(s):  
Jonathan Leis ◽  
Chi-Hao Luan ◽  
James E. Audia ◽  
Sara F. Dunne ◽  
Carissa M. Heath
Keyword(s):  
Antiviral Agents ◽  
Vero Cells ◽  
Virus Infections ◽  
Release Process ◽  
Enveloped Virus ◽  
Cells In Culture ◽  
Viral Budding ◽  
Escrt Complex ◽  
Hiv 1 ◽  
Hsv 1

In many enveloped virus families, including HIV and HSV, a crucial, yet unexploited, step in the viral life cycle is releasing particles from the infected cell membranes. This release process is mediated by host ESCRT complex proteins, which are recruited by viral structural proteins and provides the mechanical means for membrane scission and subsequent viral budding. The prazole drug, tenatoprazole, was previously shown to bind to ESCRT complex member Tsg101 and to quantitatively block the release of infectious HIV-1 from cells in culture. In this report we show that tenatoprazole and a related prazole drug, ilaprazole, effectively block infectious Herpes Simplex Virus (HSV)-1/2 release from Vero cells in culture. By electron microscopy, we found that both prazole drugs block the transit of HSV particles through the cell nuclear membrane resulting in their accumulation in the nucleus. Ilaprazole also quantitatively blocks the release of HIV-1 from 293T cells with an EC50 of 0.8-1.2 μM, which is much more potent than tenatoprazole. Our results indicate that prazole-based compounds may represent a class of drugs with potential to be broad-spectrum antiviral agents against multiple enveloped viruses, by interrupting cellular Tsg101 interaction with maturing virus, thus blocking the budding process that releases particles from the cell. Importance These results provide the basis for the development of drugs that target enveloped virus budding that can be used ultimately to control multiple virus infections in humans.

scholarly journals Ilaprazole and other novel prazole-based compounds that bind Tsg101 inhibit viral budding of HSV-1/2 and HIV from cells

2020 ◽  
Author(s):  
Jonathan Leis ◽  
Chi-Hao Luan ◽  
James E. Audia ◽  
Sara F. Dunne ◽  
Carissa M. Heath
Keyword(s):  
Antiviral Agents ◽  
Vero Cells ◽  
Virus Infections ◽  
Release Process ◽  
Enveloped Virus ◽  
Cells In Culture ◽  
Viral Budding ◽  
Escrt Complex ◽  
Hiv 1 ◽  
Hsv 1

AbstractIn many enveloped virus families, including HIV and HSV, a crucial, yet unexploited, step in the viral life cycle is releasing particles from the infected cell membranes. This release process is mediated by host ESCRT complex proteins, which is recruited by viral structural proteins and provides the mechanical means for membrane scission and subsequent viral budding. The prazole drug, tenatoprazole, was previously shown to bind to ESCRT complex member Tsg101 and quantitatively block the release of infectious HIV-1 from cells in culture. In this report we show that tenatoprazole and a related prazole drug, ilaprazole, effectively block infectious Herpes Simplex Virus (HSV)-1/2 release from Vero cells in culture. By electron microscopy, we found that both prazole drugs block the release of HSV particles from the cell nuclear membrane resulting in their accumulation in the nucleus. Ilaprazole also quantitatively blocks the release of HIV-1 from 293T cells with an EC50 of 0.8 μM, which is more potent than tenatoprazole. Finally, we synthesized and tested multiple novel prazole-based analogs that demonstrate both binding to Tsg101 and inhibition of viral egress in the nanomolar range of HIV-1 from 293T cells. Our results indicate that prazole-based compounds may represent a class of drugs with potential to be broad-spectrum antiviral agents against multiple enveloped viruses, by interrupting cellular Tsg101 interaction with maturing virus, thus blocking the budding process that releases particles from the cell.ImportanceThese results provide the basis for the development of drugs that target enveloped virus budding that can be used ultimately to control multiple virus infections in humans.

3-Hydroxyphthaloyl β-Lactoglobulin. III. Antiviral Activity against Herpesviruses

1998 ◽  
Vol 9 (2) ◽  
pp. 177-184 ◽  
Author(s):  
AR Neurath ◽  
N Strick ◽  
Y-Y Li
Keyword(s):  
Antiviral Agents ◽  
Antiviral Agent ◽  
Major Protein ◽  
Compound I ◽  
Sexually Transmitted ◽  
Prophylactic Measures ◽  
Simplex Virus ◽  
Β Lactoglobulin ◽  
Hiv 1 ◽  
Hsv 1

The spread of sexually transmitted diseases, including human immunodeficiency virus type 1 (HIV-1) and herpesvirus infections, has continued unabated despite educational efforts spearheaded as a response to the HIV-1 epidemic. This suggests the need for prophylactic measures, including the application of topical antiviral agents. Chemical modification of bovine β-lactoglobulin (β-LG), the major protein of whey, by hydroxyphthalic anhydride (3HP) led to the generation of a potent HIV-1 inhibitor (designated 3HP-β-LG) shown to also have activity against herpes simplex virus types 1 and 2 (HSV-1, HSV-2). This report provides more detailed results concerning the anti-herpesvirus activity of 3HP-β-LG, indicating that this compound: (i) inhibited infection by human cytomegalovirus (HCMV), which is known to besexually transmitted; (ii) inactivated the infectivity of both HSV-1 and HSV-2; (iii) inhibited cell-to-cell transmission of HSV-1 and HSV-2; and (iv) bound to HSV-1, HSV-2 and HCMV virus particles and partially inhibited the binding of anti-glycoprotein E (gE) and anti-gC monoclonal antibodies to HSV-1 and HSV-2. The binding of 3HP-β-LG to the herpesviruses under study was inhibited by aggregated human IgG, suggesting that the respective viral Fc receptor is one of the target sites for 3HP-β-LG. In agreement with results on inhibition of HIV-1 infection, 3HP-β-LG appears to be the acid anhydride-modified protein of choice as an antiviral agent against herpesviruses.

scholarly journals Griffithsin-Modified Electrospun Fibers as a Delivery Scaffold To Prevent HIV Infection

2016 ◽  
Vol 60 (11) ◽  
pp. 6518-6531 ◽  
Author(s):  
Tiffany N. Grooms ◽  
Hung R. Vuong ◽  
Kevin M. Tyo ◽  
Danial A. Malik ◽  
Lee B. Sims ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Antiviral Agents ◽  
Electrospun Fibers ◽  
Virus Infections ◽  
Sexually Transmitted ◽  
Treatment Regimens ◽  
Potent Inhibition ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACTDespite current prophylactic strategies, sexually transmitted infections (STIs) remain significant contributors to global health challenges, spurring the development of new multipurpose delivery technologies to protect individuals from and treat virus infections. However, there are few methods currently available to prevent and no method to date that cures human immunodeficiency virus (HIV) infection or combinations of STIs. While current oral and topical preexposure prophylaxes have protected against HIV infection, they have primarily relied on antiretrovirals (ARVs) to inhibit infection. Yet continued challenges with ARVs include user adherence to daily treatment regimens and the potential toxicity and antiviral resistance associated with chronic use. The integration of new biological agents may avert some of these adverse effects while also providing new mechanisms to prevent infection. Of the biologic-based antivirals, griffithsin (GRFT) has demonstrated potent inhibition of HIV-1 (and a multitude of other viruses) by adhering to and inactivating HIV-1 immediately upon contact. In parallel with the development of GRFT, electrospun fibers (EFs) have emerged as a promising platform for the delivery of agents active against HIV infection. In the study described here, our goal was to extend the mechanistic diversity of active agents and electrospun fibers by incorporating the biologic GRFT on the EF surface rather than within the EFs to inactivate HIV prior to cellular entry. We fabricated and characterized GRFT-modified EFs (GRFT-EFs) with different surface modification densities of GRFT and demonstrated their safety and efficacy against HIV-1 infectionin vitro. We believe that EFs are a unique platform that may be enhanced by incorporation of additional antiviral agents to prevent STIs via multiple mechanisms.

scholarly journals (Z)- and (E)-2-(Hydroxymethylcyclopropylidene)-Methylpurines and Pyrimidines as Antiviral Agents

1998 ◽  
Vol 9 (4) ◽  
pp. 57-68 ◽  
Author(s):  
Y-L Qiu ◽  
RG Ptak ◽  
JM Breitenbach ◽  
J-S Lin ◽  
Y-C Cheng ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Antiviral Agents ◽  
Human Herpesvirus ◽  
Murine Cytomegalovirus ◽  
Strong Inhibitor ◽  
Varicella Zoster ◽  
Daudi Cells ◽  
Hiv 1 ◽  
Hsv 1

Several Z- and E-methylenecyclopropane nucleoside analogues were synthesized and evaluated for antiviral activity. Reaction of the Z- and E-2-amino-6-chloropurine methylenecyclopropanes with ammonia or cyclopropylamine gave 2,6-diamino or 2-amino-6-cyclopropylamino analogues. Alkylation elimination of N4-acetylcytosine with ethyl Z- and E-2-bromo-2-bromomethylcyclopropane-1-carboxylates gave a mixture of the Z-and E-methylenecyclopropane derivatives of cytosine. Reduction furnished a mixture of syncytol and the E isomer. Benzoylation led to the respective N4-benzoyl derivatives which were separated by chromatography. Debenzoylation afforded pure syncytol and the E isomer. Alkylation of 2,4-bis-O-trimethylsilylthymine with ethyl Z- and E-2-bromo-2-bromomethylcyclopropane-1-carboxylates gave the corresponding Z- and E-1-bromo-cyclopropylmethylderivatives of thymine. Base-catalysed elimination of HBr gave Z- and E-methylenecyclopropane carboxylic esters. Reduction furnished, after chromatographic separation, synthymol and the E isomer. The Z/E isomeric assignment of the obtained products followed from 1H NMR spectroscopy. The methylenecyclopropane analogues were tested for antiviral activity in vitro against human and murine cytomegalovirus (HCMV, MCMV), Epstein–Barr virus (EBV), varicella zoster virus (VZV), hepatitis B virus (HBV), herpes simplex virus types 1 and 2 (HSV-1, HSV-2), human herpesvirus 6 (HHV-6) and human immunodeficiency virus type 1 (HIV-1). The Z-2-amino-6-cyclopropylaminopurine analogue was the most effective agent against HCMV (EC50 or EC90 0.4–2 μM) followed by syncytol and the Z-2,6-diaminopurine analogues (EC50 or EC90 3.4–29 and 11–24 μM, respectively). The latter compound was also a strong inhibitor of MCMV (EC50 0.6 μM). Syncytol was the most potent against EBV (EC50 <0.41 and 2.5 μM) followed by the Z-2,6-diaminopurine (EC50 1.5 and 6.9 μM) and the Z-2-amino-6-cyclopropylaminopurine derivative (EC50 11.8 μM). Syncytol was also most effective against VZV (EC50 3.6 μM). Activity against HSV-1, HSV-2 and HHV-6 was generally lower; synthymol had an EC50 of 2 μM against HSV-1 (ELISA) and 1.3 μM against EBV in Daudi cells but was inactive in other assays. The 2-amino-6-cyclopropylamino analogue displayed EC50 values between 215 and >74 μM in HSV-1 and HSV-2 assays. 2-Amino-6-cyclopropylaminopurine and 2,6-diaminopurine derivatives were effective against HBV (EC50 2 and 10 μM, respectively), whereas none of the analogues inhibited HIV-1 at a higher virus load. Syncytol and the E isomer were equipotent against EBV in Daudi cells but the E isomer was much less effective in DNA hybridization assays. The E-2,6-diaminopurine analogue and E isomer of synthymol were devoid of antiviral activity.

scholarly journals Innate Cellular Response to Virus Particle Entry Requires IRF3 but Not Virus Replication

2004 ◽  
Vol 78 (4) ◽  
pp. 1706-1717 ◽  
Author(s):  
Susan E. Collins ◽  
Ryan S. Noyce ◽  
Karen L. Mossman
Keyword(s):  
Virus Replication ◽  
Mammalian Cells ◽  
Cellular Response ◽  
Sendai Virus ◽  
Antiviral Response ◽  
Interferon Production ◽  
Virus Infections ◽  
Mrna Accumulation ◽  
Enveloped Virus ◽  
Hsv 1

ABSTRACT Mammalian cells respond to virus infections by eliciting both innate and adaptive immune responses. One of the most effective innate antiviral responses is the production of alpha/beta interferon and the subsequent induction of interferon-stimulated genes (ISGs), whose products collectively limit virus replication and spread. Following viral infection, interferon is produced in a biphasic fashion that involves a number of transcription factors, including the interferon regulatory factors (IRFs) 1, 3, 7, and 9. In addition, virus infection has been shown to directly induce ISGs in the absence of prior interferon production through the activation of IRF3. This process is believed to require virus replication and results in IRF3 hyperphosphorylation, nuclear localization, and proteasome-mediated degradation. Previously, we and others demonstrated that herpes simplex virus type 1 (HSV-1) induces ISGs and an antiviral response in fibroblasts in the absence of both interferon production and virus replication. In this report, we show that the entry of enveloped virus particles from diverse virus families elicits a similar innate response. This process requires IRF3, but not IRF1, IRF7, or IRF9. Following virus replication, the large DNA viruses HSV-1 and vaccinia virus effectively inhibit ISG mRNA accumulation, whereas the small RNA viruses Newcastle disease virus, Sendai virus, and vesicular stomatitis virus do not. In addition, we found that IRF3 hyperphosphorylation and degradation do not correlate with ISG and antiviral state induction but instead serve as a hallmark of productive virus replication, particularly following a high-multiplicity infection. Collectively, these data suggest that virus entry triggers an innate antiviral response mediated by IRF3 and that subsequent virus replication results in posttranslational modification of IRF3, such as hyperphosphorylation, depending on the nature of the incoming virus.

scholarly journals Potential antiviral agents of Rosmarinus officinalis extract against herpes viruses 1 and 2

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Wafa A. AL-Megrin ◽  
Norah A. AlSadhan ◽  
Dina M. Metwally ◽  
Razan A. Al-Talhi ◽  
Manal F. El-Khadragy ◽  
...  
Keyword(s):  
Superoxide Anion ◽  
Viral Infections ◽  
Antiviral Agents ◽  
Vero Cells ◽  
Rosmarinus Officinalis ◽  
Rosemary Extract ◽  
Scavenging Activity ◽  
Herpes Simplex Viruses ◽  
Hsv 1

Abstract Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) belong to the herpesviridae family and cause neurological disorders by infecting the nervous system. The present study aimed to investigate the effects of Rosmarinus officinalis L. (rosemary) extract against HSV-1 and HSV-2 in vitro. The antioxidant activity of this extract was investigated by superoxide anion and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free-radical assays. Rosemary extract was evaluated by an HSV-1 antiviral assay, in which viral replication in Vero cells was determined and quantified using a cytopathic effect assay. The present study showed that rosemary extract at 30 µg/ml caused 55% inhibition of HSV-1 plaques, whereas 40 µg/ml rosemary extract caused 65% inhibition of HSV-2 plaques. The extracts completely inhibited HSV-1 and HSV-2 plaque formation at 50 µg/ml. Scavenging activity of the superoxide anion radical was observed at 65.74 mg/ml, whereas 50% scavenging activity of the DPPH radical was observed at 67.34 mg/ml. These data suggest that rosemary extract may be suitable as a topical prophylactic or therapeutic agent for herpes viral infections. However, further research is required to elucidate the plant’s active constituents, which may be useful in drug development.

scholarly journals Combination of CCR5 and CXCR4 Inhibitors in Therapy of Human Immunodeficiency Virus Type 1 Infection: In Vitro Studies of Mixed Virus Infections

2000 ◽  
Vol 74 (19) ◽  
pp. 9328-9332 ◽  
Author(s):  
Stefano Rusconi ◽  
Simona La Seta Catamancio ◽  
Paola Citterio ◽  
Elisabetta Bulgheroni ◽  
Francesco Croce ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Opposite Effect ◽  
Antiviral Agents ◽  
Virus Infections ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT We studied the combined anti-human immunodeficiency virus type 1 (HIV-1) effects of a derivative of stroma-derived factor 1β (SDF-1β), Met-SDF-1β, and a modified form of RANTES, aminooxypentane (AOP)-RANTES. The antiviral agents were tested singly or in combination at 95 and 99% virus inhibitory concentrations. Clinical R5 and X4 HIV-1 isolates were used. AOP-RANTES inhibited R5 but not X4 viruses, whereas Met-SDF-1β had the opposite effect. Combinations of these compounds inhibited mixed infections with R5 and X4 viruses (95 to 99%), whereas single drugs were less inhibitory (32 to 61%). Combinations of R5 and X4 inhibitors are promising and deserve further evaluation.

scholarly journals Heparin Inhibits Cellular Invasion by SARS-CoV-2: Structural Dependence of the Interaction of the Spike S1 Receptor-Binding Domain with Heparin

2020 ◽  
Vol 120 (12) ◽  
pp. 1700-1715
Author(s):  
Courtney J. Mycroft-West ◽  
Dunhao Su ◽  
Isabel Pagani ◽  
Timothy R. Rudd ◽  
Stefano Elli ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Structural Changes ◽  
Rapid Development ◽  
Antiviral Agents ◽  
Vero Cells ◽  
Binding Domain ◽  
Microbial Pathogens ◽  
Minimum Size ◽  
Structural Basis ◽  
Receptor Binding Domain

AbstractThe dependence of development and homeostasis in animals on the interaction of hundreds of extracellular regulatory proteins with the peri- and extracellular glycosaminoglycan heparan sulfate (HS) is exploited by many microbial pathogens as a means of adherence and invasion. Heparin, a widely used anticoagulant drug, is structurally similar to HS and is a common experimental proxy. Exogenous heparin prevents infection by a range of viruses, including S-associated coronavirus isolate HSR1. Here, we show that heparin inhibits severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) invasion of Vero cells by up to 80% at doses achievable through prophylaxis and, particularly relevant, within the range deliverable by nebulisation. Surface plasmon resonance and circular dichroism spectroscopy demonstrate that heparin and enoxaparin, a low-molecular-weight heparin which is a clinical anticoagulant, bind and induce a conformational change in the spike (S1) protein receptor-binding domain (S1 RBD) of SARS-CoV-2. A library of heparin derivatives and size-defined fragments were used to probe the structural basis of this interaction. Binding to the RBD is more strongly dependent on the presence of 2-O or 6-O sulfate groups than on N-sulfation and a hexasaccharide is the minimum size required for secondary structural changes to be induced in the RBD. It is likely that inhibition of viral infection arises from an overlap between the binding sites of heparin/HS on S1 RBD and that of the angiotensin-converting enzyme 2. The results suggest a route for the rapid development of a first-line therapeutic by repurposing heparin and its derivatives as antiviral agents against SARS-CoV-2 and other members of the Coronaviridae.

scholarly journals Phytochemical Characterization of Olea europea Leaf Extracts and Assessment of Their Anti-Microbial and Anti-HSV-1 Activity

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1085
Author(s):  
Ichrak Ben-Amor ◽  
Maria Musarra-Pizzo ◽  
Antonella Smeriglio ◽  
Manuela D’Arrigo ◽  
Rosamaria Pennisi ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Viral Entry ◽  
Antiviral Effect ◽  
Vero Cells ◽  
Biological Properties ◽  
Leaf Extracts ◽  
Gram Positive Bacteria ◽  
Entry Assay ◽  
Olea Europea ◽  
Hsv 1

Owing to the richness of bioactive compounds, Olea europea leaf extracts exhibit a range of health effects. The present research evaluated the antibacterial and antiviral effect of leaf extracts obtained from Olea europea L. var. sativa (OESA) and Olea europea var. sylvestris (OESY) from Tunisia. LC-DAD-ESI-MS analysis allowed the identification of different compounds that contributed to the observed biological properties. Both OESA and OESY were active against Gram-positive bacteria (MIC values between 7.81 and 15.61 μg/mL and between 15.61 and 31.25 μg/mL against Staphylococcus aureus ATCC 6538 for OESY and OESA, respectively). The antiviral activity against the herpes simplex type 1 (HSV-1) was assessed on Vero cells. The results of cell viability indicated that Olea europea leaf extracts were not toxic to cultured Vero cells. The half maximal cytotoxic concentration (CC50) values for OESA and OESY were 0.2 mg/mL and 0.82 mg/mL, respectively. Furthermore, both a plaque reduction assay and viral entry assay were used to demonstrate the antiviral activity. In conclusion, Olea europea leaf extracts demonstrated a bacteriostatic effect, as well as remarkable antiviral activity, which could provide an alternative treatment against resistant strains.

scholarly journals Salidroside Protects Against Influenza A Virus-Induced Acute Lung Injury in Mice

Dose-Response ◽  
2021 ◽  
Vol 19 (2) ◽  
pp. 155932582110113
Author(s):  
Rufeng Lu ◽  
Yueguo Wu ◽  
Honggang Guo ◽  
Zhuoyi Zhang ◽  
Yuzhou He
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Influenza A Virus ◽  
Influenza A ◽  
H1n1 Virus ◽  
Antiviral Agents ◽  
Toll Like Receptor ◽  
Virus Infections ◽  
Toll Like Receptor 4 ◽  
Inflammatory Cytokine Production

Influenza A virus infections can cause acute lung injury (ALI) in humans; thus, the identification of potent antiviral agents is urgently required. Herein, the effects of salidroside on influenza A virus-induced ALI were investigated in a murine model. BALB/c mice were intranasally inoculated with H1N1 virus and treated with salidroside. The results of this study show that salidroside treatment (30 and 60 mg/kg) significantly attenuated the H1N1 virus-induced histological alterations in the lung and inhibited inflammatory cytokine production. Salidroside also decreased the wet/dry ratio, viral titers, and Toll-like receptor 4 expression in the lungs. Therefore, salidroside may represent a potential therapeutic reagent for the treatment of influenza A virus-induced ALI.

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