scholarly journals Nanodroplet-Benzalkonium Chloride Formulation Demonstrates In Vitro and Ex- Vivo Broad-Spectrum Antiviral Activity Against SARS-CoV-2 and other Enveloped Viruses

2021 ◽  
Author(s):  
Jessie Pannu ◽  
Susan Ciotti ◽  
Shyamala Ganesan ◽  
George Arida ◽  
Chad Costley ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Broad Spectrum ◽  
Benzalkonium Chloride ◽  
Ex Vivo ◽  
Viral Disease ◽  
Influenza B ◽  
Human Coronavirus ◽  
Enveloped Viruses ◽  
Nasal Irritation

Abstract Objective: The Covid-19 pandemic has highlighted the importance of aerosolized droplets inhaled into the nose in the transmission of respiratory viral disease. Inactivating pathogenic viruses at the nasal port of entry may reduce viral loads, thereby reducing infection, transmission and spread. In this communication, we demonstrate safe and broad anti-viral activity of oil-in-water nanoemulsion (nanodroplet) formulation containing the potent antiseptic 0.13% Benzalkonium Chloride (NE-BZK). Results: We have demonstrated that NE-BZK exhibits broad-spectrum, long-lasting antiviral activity with >99.9% in vitro killing of enveloped viruses including SARS-CoV-2, human coronavirus, RSV, and influenza B. In vitro and ex-vivo studies demonstrated continued killing of >99.99% of human coronavirus with diluted NE-BZK and persistent for 8 hours post application, respectively. The repeated application of NE-BZK, twice daily for 2 weeks into rabbit nostrils demonstrated its safety with no nasal irritation. These findings demonstrate that formulating BZK into the proprietary nanodroplets offers a safe and effective antiviral and a significant addition to strategies to combat the spread of respiratory viral infectious diseases.

scholarly journals Nanodroplet-Benzalkonium Chloride Formulation Demonstrates In Vitro and Ex-Vivo Broad-Spectrum Antiviral Activity Against SARS-CoV-2 and other Enveloped Viruses

2020 ◽  
Author(s):  
Jessie Pannu ◽  
Susan Ciotti ◽  
Shyamala Ganesan ◽  
George Arida ◽  
Chad Costley ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Broad Spectrum ◽  
Benzalkonium Chloride ◽  
Ex Vivo ◽  
Viral Disease ◽  
Influenza B ◽  
Human Coronavirus ◽  
Enveloped Viruses ◽  
Cadaver Skin

AbstractThe Covid-19 pandemic has highlighted the importance of aerosolized droplets inhaled into the nose in the transmission of respiratory viral disease. Inactivating pathogenic viruses at the nasal portal of entry may reduce viral loads, thereby reducing transmission and contagion. We have developed an oil-in-water nanoemulsion (nanodroplet) formulation containing the potent antiseptic 0.13% Benzalkonium Chloride (NE-BZK) which demonstrates safe and broad anti-viral activity. While The Centers for Disease Control and Prevention (CDC) have reported that BZK may have less reliable activity than ethyl alcohol against certain viruses, including coronaviruses, we have demonstrated that NE-BZK exhibits broad-spectrum, long-lasting antiviral activity with >99.99% in vitro killing of enveloped viruses including SARS-CoV-2, human coronavirus, RSV and influenza B. Furthermore, in vitro studies demonstrated that NE-BZK continues to kill >99.99% of human coronavirus even when diluted 20-fold, while 0.13% aqueous BZK solution (AQ-BZK) did not. Ex vivo studies of NE-BZK on human cadaver skin demonstrated persistent >99.99% killing of human coronavirus for at least 8 hours after application. AQ-BZK failed to demonstrate durable antimicrobial activity on skin over time. The repeated application of NE-BZK, twice daily for 2 weeks on to rabbit nostrils indicated safety with no irritation. These findings demonstrate that formulating BZK on the surface of proprietary nanodroplets offers a safe and effective antiviral as a significant addition to strategies to combat the spread of respiratory viral infectious diseases.

scholarly journals Broad-Spectrum Antiviral Entry Inhibition by Interfacially Active Peptides

2020 ◽  
Vol 94 (23) ◽  
Author(s):  
Andrew R. Hoffmann ◽  
Shantanu Guha ◽  
Eric Wu ◽  
Jenisha Ghimire ◽  
Yilin Wang ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Broad Spectrum ◽  
Mammalian Cells ◽  
Viral Disease ◽  
Antiviral Drugs ◽  
Viral Envelope ◽  
Molecular Characteristics ◽  
Enveloped Viruses ◽  
Interfacial Activity ◽  
Active Peptides

ABSTRACT Numerous peptides inhibit the entry of enveloped viruses into cells. Some of these peptides have been shown to inhibit multiple unrelated viruses. We have suggested that such broad-spectrum antiviral peptides share a property called interfacial activity; they are somewhat hydrophobic and amphipathic, with a propensity to interact with the interfacial zones of lipid bilayer membranes. In this study, we further tested the hypothesis that such interfacial activity is a correlate of broad-spectrum antiviral activity. In this study, several families of peptides, selected for the ability to partition into and disrupt membrane integrity but with no known antiviral activity, were tested for the ability to inhibit multiple diverse enveloped viruses. These include Lassa pseudovirus, influenza virus, dengue virus type 2, herpes simplex virus 1, and nonenveloped human adenovirus 5. Various families of interfacially active peptides caused potent inhibition of all enveloped viruses tested at low and submicromolar concentrations, well below the range in which they are toxic to mammalian cells. These membrane-active peptides block uptake and fusion with the host cell by rapidly and directly interacting with virions, destabilizing the viral envelope, and driving virus aggregation and/or intervirion envelope fusion. We speculate that the molecular characteristics shared by these peptides can be exploited to enable the design, optimization, or molecular evolution of novel broad-spectrum antiviral therapeutics. IMPORTANCE New classes of antiviral drugs are needed to treat the ever-changing viral disease landscape. Current antiviral drugs treat only a small number of viral diseases, leaving many patients with established or emerging infections to be treated solely with supportive care. Recent antiviral peptide research has produced numerous membrane-interacting peptides that inhibit diverse enveloped viruses in vitro and in vivo. Peptide therapeutics are becoming more common, with over 60 FDA-approved peptides for clinical use. Included in this class of therapeutics is enfuvirtide, a 36-residue peptide drug that inhibits HIV entry/fusion. Due to their broad-spectrum mechanism of action and enormous potential sequence diversity, peptides that inhibit virus entry could potentially fulfill the need for new antiviral therapeutics; however, a better understanding of their mechanism is needed for the optimization or evolution of sequence design to combat the wide landscape of viral disease.

scholarly journals Broad-Spectrum Antiviral Activity of 3D8, a Nucleic Acid-Hydrolyzing Single-Chain Variable Fragment (scFv), Targeting SARS-CoV-2 and Multiple Coronaviruses In Vitro

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 650
Author(s):  
Gunsup Lee ◽  
Shailesh Budhathoki ◽  
Geum-Young Lee ◽  
Kwang-ji Oh ◽  
Yeon Kyoung Ham ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Antiviral Activity ◽  
Broad Spectrum ◽  
Recombinant Antibody ◽  
Therapeutic Effects ◽  
Single Chain Variable Fragment ◽  
Single Chain ◽  
Diarrhea Virus ◽  
3D8 Scfv

The virus behind the current pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the etiology of novel coronavirus disease (COVID-19) and poses a critical public health threat worldwide. Effective therapeutics and vaccines against multiple coronaviruses remain unavailable. Single-chain variable fragment (scFv), a recombinant antibody, exhibits broad-spectrum antiviral activity against DNA and RNA viruses owing to its nucleic acid-hydrolyzing property. The antiviral activity of 3D8 scFv against SARS-CoV-2 and other coronaviruses was evaluated in Vero E6 cell cultures. Viral growth was quantified with quantitative RT-qPCR and plaque assay. The nucleic acid-hydrolyzing activity of 3D8 was assessed through abzyme assays of in vitro viral transcripts and cell viability was determined by MTT assay. We found that 3D8 inhibited the replication of SARS-CoV-2, human coronavirus OC43 (HCoV-OC43), and porcine epidemic diarrhea virus (PEDV). Our results revealed the prophylactic and therapeutic effects of 3D8 scFv against SARS-CoV-2 in Vero E6 cells. Immunoblot and plaque assays showed the reduction of coronavirus nucleoproteins and infectious particles, respectively, in 3D8 scFv-treated cells. These data demonstrate the broad-spectrum antiviral activity of 3D8 against SARS-CoV-2 and other coronaviruses. Thus, it could be considered a potential antiviral countermeasure against SARS-CoV-2 and zoonotic coronaviruses.

scholarly journals Non-Toxic Virucidal Macromolecules Show High Efficacy Against Influenza Virus Ex Vivo and In Vivo

2020 ◽  
Author(s):  
Ozgun Kocabiyik ◽  
Valeria Cagno ◽  
Paulo Jacob Silva ◽  
Yong Zhu ◽  
Laura Sedano ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Viral Infections ◽  
Ex Vivo ◽  
Public Health Problem ◽  
Major Public Health Problem ◽  
New Class ◽  
Influenza Strain ◽  
Low Toxicity

AbstractInfluenza is one of the most widespread viral infections worldwide and represents a major public health problem. The risk that one of the next pandemics is caused by an influenza strain is very high. It is very important to develop broad-spectrum influenza antivirals to be ready for any possible vaccine shortcomings. Anti-influenza drugs are available but they are far from ideal. Arguably, an ideal antiviral should target conserved viral domains and be virucidal, i.e. irreversibly inhibit viral infectivity. Here, we describe a new class of broad-spectrum anti-influenza macromolecules that meets these criteria and displays exceedingly low toxicity. These compounds are based on a cyclodextrin core modified on its primary face with long hydrophobic linkers terminated in 6’sialyl-N-acetyllactosamine (6’SLN) or 3’SLN. SLN enables nanomolar inhibition of the viruses while the hydrophobic linkers confer irreversibility to the inhibition. The combination of these two properties allows for efficacy in vitro against several human or avian influenza strains, as well as against a 2009 pandemic influenza strain ex vivo. Importantly, we show that, in mice, the compounds provide therapeutic efficacy when administered 24h post-infection allowing 90% survival as opposed to no survival for the placebo and oseltamivir..

scholarly journals Identification and Characterization of Novel Compounds with Broad-Spectrum Antiviral Activity against Influenza A and B Viruses

2020 ◽  
Vol 94 (7) ◽  
Author(s):  
Jun-Gyu Park ◽  
Ginés Ávila-Pérez ◽  
Aitor Nogales ◽  
Pilar Blanco-Lobo ◽  
Juan C. de la Torre ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Rna Polymerase Ii ◽  
Broad Spectrum ◽  
Influenza A ◽  
Viral Infections ◽  
Influenza Infection ◽  
Inhibitory Effect ◽  
Influenza Viruses ◽  
Influenza B ◽  
Genome Replication

ABSTRACT Influenza A (IAV) and influenza B (IBV) viruses are highly contagious pathogens that cause fatal respiratory disease every year, with high economic impact. In addition, IAV can cause pandemic infections with great consequences when new viruses are introduced into humans. In this study, we evaluated 10 previously described compounds with antiviral activity against mammarenaviruses for their ability to inhibit IAV infection using our recently described bireporter influenza A/Puerto Rico/8/34 (PR8) H1N1 (BIRFLU). Among the 10 tested compounds, eight (antimycin A [AmA], brequinar [BRQ], 6-azauridine, azaribine, pyrazofurin [PF], AVN-944, mycophenolate mofetil [MMF], and mycophenolic acid [MPA]), but not obatoclax or Osu-03012, showed potent anti-influenza virus activity under posttreatment conditions [median 50% effective concentration (EC50) = 3.80 nM to 1.73 μM; selective index SI for 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, >28.90 to 13,157.89]. AmA, 6-azauridine, azaribine, and PF also showed potent inhibitory effect in pretreatment (EC50 = 0.14 μM to 0.55 μM; SI-MTT = 70.12 to >357.14) or cotreatment (EC50 = 34.69 nM to 7.52 μM; SI-MTT = 5.24 to > 1,441.33) settings. All of the compounds tested inhibited viral genome replication and gene transcription, and none of them affected host cellular RNA polymerase II activities. The antiviral activity of the eight identified compounds against BIRFLU was further confirmed with seasonal IAVs (A/California/04/2009 H1N1 and A/Wyoming/3/2003 H3N2) and an IBV (B/Brisbane/60/2008, Victoria lineage), demonstrating their broad-spectrum prophylactic and therapeutic activity against currently circulating influenza viruses in humans. Together, our results identified a new set of antiviral compounds for the potential treatment of influenza viral infections. IMPORTANCE Influenza viruses are highly contagious pathogens and are a major threat to human health. Vaccination remains the most effective tool to protect humans against influenza infection. However, vaccination does not always guarantee complete protection against drifted or, more noticeably, shifted influenza viruses. Although U.S. Food and Drug Administration (FDA) drugs are approved for the treatment of influenza infections, influenza viruses resistant to current FDA antivirals have been reported and continue to emerge. Therefore, there is an urgent need to find novel antivirals for the treatment of influenza viral infections in humans, a search that could be expedited by repurposing currently approved drugs. In this study, we assessed the influenza antiviral activity of 10 compounds previously shown to inhibit mammarenavirus infection. Among them, eight drugs showed antiviral activities, providing a new battery of drugs that could be used for the treatment of influenza infections.

scholarly journals Broad-Spectrum Antiviral Activity of 3’-Deoxy-3’-Fluoroadenosine against Emerging Flaviviruses

2020 ◽  
Author(s):  
Luděk Eyer ◽  
Pavel Svoboda ◽  
Jan Balvan ◽  
Tomáš Vičar ◽  
Matina Raudenská ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Broad Spectrum ◽  
Nucleotide Metabolism ◽  
Modified Nucleosides ◽  
Bioactive Molecules ◽  
Nucleoside Analogues ◽  
Phase Imaging ◽  
Structural And Functional Properties

Emerging flaviviruses are causative agents of severe and life-threatening diseases, against which no approved therapies are available. Among the nucleoside analogues, which represent a promising group of potentially therapeutic compounds, fluorine-substituted nucleosides are characterized by unique structural and functional properties. Despite having been first synthesized almost 5 decades ago, they still offer new therapeutic opportunities as inhibitors of essential viral or cellular enzymes active in nucleic acid replication/transcription or nucleoside/nucleotide metabolism. Here we report evaluation of the anti-flaviviral activity of 28 nucleoside analogues, each modified with a fluoro substituent at different positions of the ribose ring and/or heterocyclic nucleobase. Our antiviral screening revealed that 3′-deoxy-3′-fluoroadenosine exerted a low-micromolar antiviral effect against tick-borne encephalitis virus (TBEV), Zika virus, and West Nile (WNV) virus (EC50 values from 1.1 ± 0.1 μM to 4.7 ± 1.5 μM), which was manifested in host cell lines of neural and extraneural origin. The compound did not display any measurable cytotoxicity up to concentrations of 25 μM but had an observable cytostatic effect, resulting in suppression of cell proliferation at concentrations of >12.5 μM. Novel approaches based on quantitative phase imaging using holographic microscopy were developed for advanced characterization of antiviral and cytotoxic profiles of 3′-deoxy-3′-fluoroadenosine in vitro. In addition to its antiviral activity in cell cultures, 3′-deoxy-3′-fluoroadenosine was active in vivo in mouse models of TBEV and WNV infection. Our results demonstrate that fluoro-modified nucleosides represent a group of bioactive molecules with excellent potential to serve as prospective broad-spectrum antivirals in antiviral research and drug development.

scholarly journals Modified cyclodextrins as broad-spectrum antivirals

2020 ◽  
Vol 6 (5) ◽  
pp. eaax9318 ◽  
Author(s):  
Samuel T. Jones ◽  
Valeria Cagno ◽  
Matej Janeček ◽  
Daniel Ortiz ◽  
Natalia Gasilova ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Viral Infections ◽  
Ex Vivo ◽  
Vaginal Tissue ◽  
Modified Cyclodextrins ◽  
Culture Models ◽  
Heparan Sulfates ◽  
Syncytial Virus ◽  
Simplex Virus

Viral infections kill millions of people and new antivirals are needed. Nontoxic drugs that irreversibly inhibit viruses (virucidal) are postulated to be ideal. Unfortunately, all virucidal molecules described to date are cytotoxic. We recently developed nontoxic, broad-spectrum virucidal gold nanoparticles. Here, we develop further the concept and describe cyclodextrins, modified with mercaptoundecane sulfonic acids, to mimic heparan sulfates and to provide the key nontoxic virucidal action. We show that the resulting macromolecules are broad-spectrum, biocompatible, and virucidal at micromolar concentrations in vitro against many viruses [including herpes simplex virus (HSV), respiratory syncytial virus (RSV), dengue virus, and Zika virus]. They are effective ex vivo against both laboratory and clinical strains of RSV and HSV-2 in respiratory and vaginal tissue culture models, respectively. Additionally, they are effective when administrated in mice before intravaginal HSV-2 inoculation. Lastly, they pass a mutation resistance test that the currently available anti-HSV drug (acyclovir) fails.

scholarly journals Amphipathic DNA Polymers Exhibit Antiherpetic Activity In Vitro and In Vivo

2008 ◽  
Vol 52 (8) ◽  
pp. 2727-2733 ◽  
Author(s):  
David I. Bernstein ◽  
Nathalie Goyette ◽  
Rhonda Cardin ◽  
Earl R. Kern ◽  
Guy Boivin ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Broad Spectrum ◽  
Parent Compound ◽  
Human Herpesvirus ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Simplex Virus ◽  
Acid Stable

ABSTRACT Phosphorothioated oligonucleotides have a sequence-independent antiviral activity as amphipathic polymers (APs). The activity of these agents against herpesvirus infections in vitro and in vivo was investigated. The previously established sequence-independent, phosphorothioation-dependent antiviral activity of APs was confirmed in vitro by showing that a variety of equivalently sized homo- and heteropolymeric AP sequences were similarly active against herpes simplex virus type 1 (HSV-1) infection in vitro compared to the 40mer degenerate parent compound (REP 9), while the absence of phosphorothioation resulted in the loss of antiviral activity. In addition, REP 9 demonstrated in vitro activity against a broad spectrum of other herpesviruses: HSV-2 (50% effective concentration [EC50], 0.02 to 0.06 μM), human cytomegalovirus (EC50, 0.02 to 0.13 μM), varicella zoster virus (EC50, <0.02 μM), Epstein-Barr virus (EC50, 14.7 μM) and human herpesvirus types 6A/B (EC50, 2.9 to 10.2 μM). The murine microbicide model of genital HSV-2 was then used to evaluate in vivo activity. REP 9 (275 mg/ml) protected 75% of animals from disease and infection when provided 5 or 30 min prior to vaginal challenge. When an acid-stable analog (REP 9C) was used, 75% of mice were protected when treated with 240 mg/ml 5 min prior to infection (P < 0.001), while a lower dose (100 mg/ml) protected 100% of the mice (P < 0.001). The acid stable REP 9C formulation also provided protection at 30 min (83%, P < 0.001) and 60 min (50%, P = 0.07) against disease. These observations suggest that APs may have microbicidal activity and potential as broad-spectrum antiherpetic agents and represent a novel class of agents that should be studied further.

scholarly journals Vaginal Microbicide Gel for Delivery of IQP-0528, a Pyrimidinedione Analog with a Dual Mechanism of Action against HIV-1

2011 ◽  
Vol 55 (4) ◽  
pp. 1650-1660 ◽  
Author(s):  
Alamelu Mahalingam ◽  
Adam P. Simmons ◽  
Shweta R. Ugaonkar ◽  
Karen M. Watson ◽  
Charlene S. Dezzutti ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Mechanical Stability ◽  
Culture Media ◽  
Ex Vivo ◽  
Hydroxyethyl Cellulose ◽  
Therapeutic Window ◽  
Formulation Development ◽  
Drug Release Profile ◽  
Hiv 1

ABSTRACTPyrimidinediones, a novel class of compounds, have previously been shown to possess antiviral activity at nanomolar concentrations. One member of this class of compounds, IQP-0528, was selected as the lead molecule for formulation development owing to its stability at physiologically relevant conditions, wide therapeutic window, and antiviral activity in the nanomolar range. Here, we report the development of two vaginal gels—3.0% hydroxyethyl cellulose (HEC) formulation and a 0.65% Carbopol formulation—for the sustained delivery of IQP-0528. Stability studies under accelerated conditions confirmed the chemical stability of IQP-0528 and mechanical stability of the gel formulation for 3 months.In vitrorelease studies revealed that diffusion-controlled release of IQP-0528 occurred over 6 h, with an initial lag time of approximately 1 h. Based on the drug release profile, the 3.0% HEC gel was selected as the lead formulation for safety and activity evaluations. Thein vitroandex vivosafety evaluations showed no significant loss in cell viability or significant inflammatory response after treatment with a 3.0% HEC gel containing 0.25% IQP-0528. In anin vitroHIV-1 entry inhibition assay, the lead formulation showed an 50% effective concentration of 0.14 μg/ml for gel in culture media, which corresponds to ∼0.001 μM IQP-0528. The antiviral activity was further confirmed by using polarized cervical explants, in which the formulation showed complete protection against HIV infection. In summary, these results are encouraging and warrant further evaluation of IQP-0528 gel formulations inin vivomodels, as well as the development of alternative formulations for the delivery of IQP-0528 as a microbicide.

scholarly journals Activity of and Effect of Subcutaneous Treatment with the Broad-Spectrum Antiviral Lectin Griffithsin in Two Laboratory Rodent Models

2013 ◽  
Vol 58 (1) ◽  
pp. 120-127 ◽  
Author(s):  
Christopher Barton ◽  
J. Calvin Kouokam ◽  
Amanda B. Lasnik ◽  
Oded Foreman ◽  
Alexander Cambon ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Broad Spectrum ◽  
Ebola Virus ◽  
Viral Infections ◽  
Antiviral Treatment ◽  
Enveloped Viruses ◽  
Minimal Toxicity ◽  
Human T Cell ◽  
Long Term Treatment ◽  
Hiv 1

ABSTRACTGriffithsin (GRFT) is a red-alga-derived lectin that binds the terminal mannose residues of N-linked glycans found on the surface of human immunodeficiency virus type 1 (HIV-1), HIV-2, and other enveloped viruses, including hepatitis C virus (HCV), severe acute respiratory syndrome coronavirus (SARS-CoV), and Ebola virus. GRFT displays no human T-cell mitogenic activity and does not induce production of proinflammatory cytokines in treated human cell lines. However, despite the growing evidence showing the broad-spectrum nanomolar or better antiviral activity of GRFT, no study has reported a comprehensive assessment of GRFT safety as a potential systemic antiviral treatment. The results presented in this work show that minimal toxicity was induced by a range of single and repeated daily subcutaneous doses of GRFT in two rodent species, although we noted treatment-associated increases in spleen and liver mass suggestive of an antidrug immune response. The drug is systemically distributed, accumulating to high levels in the serum and plasma after subcutaneous delivery. Further, we showed that serum from GRFT-treated animals retained antiviral activity against HIV-1-enveloped pseudoviruses in a cell-based neutralization assay. Overall, our data presented here show that GRFT accumulates to relevant therapeutic concentrations which are tolerated with minimal toxicity. These studies support further development of GRFT as a systemic antiviral therapeutic agent against enveloped viruses, although deimmunizing the molecule may be necessary if it is to be used in long-term treatment of chronic viral infections.

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