A mastoparan-derived peptide has broad-spectrum antiviral activity against enveloped viruses

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.

Download Full-text

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01407-13 ◽

2013 ◽

Vol 58 (1) ◽

pp. 120-127 ◽

Cited By ~ 61

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.

Download Full-text

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

10.1101/2020.11.12.377598 ◽

2020 ◽

Cited By ~ 1

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.

Download Full-text

Broad-Spectrum Antiviral Entry Inhibition by Interfacially Active Peptides

Journal of Virology ◽

10.1128/jvi.01682-20 ◽

2020 ◽

Vol 94 (23) ◽

Cited By ~ 1

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.

Download Full-text

Broad-spectrum antiviral activity of polyoxometalates against human immunodeficiency virus and other enveloped viruses

Antiviral Research ◽

10.1016/0166-3542(92)90140-z ◽

1992 ◽

Vol 17 ◽

pp. 65

Keyword(s):

Human Immunodeficiency Virus ◽

Antiviral Activity ◽

Broad Spectrum ◽

Enveloped Viruses ◽

Immunodeficiency Virus

Download Full-text

Faculty Opinions recommendation of Mechanism-based covalent neuraminidase inhibitors with broad-spectrum influenza antiviral activity.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717980442.793471723 ◽

2013 ◽

Author(s):

Xiayang Qiu ◽

Ye Che

Keyword(s):

Antiviral Activity ◽

Broad Spectrum ◽

Neuraminidase Inhibitors

Download Full-text

Antiviral activity of uridine 5′-diphosphate glucose analogues against some enveloped viruses in cell culture

Antiviral Research ◽

10.1016/s0166-3542(87)80007-4 ◽

1987 ◽

Vol 8 (5-6) ◽

pp. 299-310 ◽

Cited By ~ 11

Author(s):

G. Gil-Fernández ◽

S. Pérez ◽

P. Vilas ◽

C. Pérez ◽

F.G. de las Heras ◽

...

Keyword(s):

Cell Culture ◽

Antiviral Activity ◽

Enveloped Viruses ◽

Glucose Analogues ◽

Diphosphate Glucose

Download Full-text

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 ◽

10.3390/v13040650 ◽

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.

Download Full-text

The effectiveness of antiviral agents with broad-spectrum activity against chikungunya virus varies between host cell lines

Antiviral Chemistry and Chemotherapy ◽

10.1177/2040206618807580 ◽

2018 ◽

Vol 26 ◽

pp. 204020661880758 ◽

Cited By ~ 14

Author(s):

Evelyn J Franco ◽

Jaime L Rodriquez ◽

Justin J Pomeroy ◽

Kaley C Hanrahan ◽

Ashley N Brown

Keyword(s):

Antiviral Activity ◽

Host Cell ◽

Cell Line ◽

Cell Lines ◽

Broad Spectrum ◽

Chikungunya Virus ◽

Plaque Assay ◽

A549 Cells ◽

Western Hemisphere ◽

Viral Burden

Chikungunya virus (CHIKV) is a mosquito-borne virus that has recently emerged in the Western Hemisphere. Approved antiviral therapies or vaccines for the treatment or prevention of CHIKV infections are not available. This study aims to evaluate the antiviral activity of commercially available broad-spectrum antivirals against CHIKV. Due to host cell-specific variability in uptake and intracellular processing of drug, we evaluated the antiviral effects of each agent in three cell lines. Antiviral activities of ribavirin (RBV), interferon-alfa (IFN-α) and favipiravir (FAV) were assessed in CHIKV-infected Vero, HUH-7, and A549 cells. CHIKV-infected cells were treated with increasing concentrations of each agent for three days and viral burden was quantified by plaque assay on Vero cells. Cytotoxic effects of RBV, FAV and IFN-α were also evaluated. Antiviral activity differed depending on the cell line used for evaluation. RBV had the greatest antiviral effect in HUH-7 cells (EC50 = 2.575 µg/mL); IFN-α was most effective in A549 cells (EC50 = 4.235 IU/mL); and FAV in HUH-7 cells (EC50 = 20.00 μg/mL). The results of our study show FAV and IFN-α are the most promising candidates, as their use led to substantial reductions in viral burden at clinically achievable concentrations in two human-derived cell lines. FAV is an especially attractive candidate for further investigation due to its oral bioavailability. These findings also highlight the importance of cell line selection for preclinical drug trials.

Download Full-text