scholarly journals Broad-Spectrum In Vitro Antiviral Activity of ODBG-P-RVn: An Orally-Available, Lipid-Modified Monophosphate Prodrug of Remdesivir Parent Nucleoside (GS-441524)

2021 ◽  
Author(s):  
Michael K. Lo ◽  
Punya Shrivastava-Ranjan ◽  
Payel Chatterjee ◽  
Mike Flint ◽  
James R. Beadle ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Broad Spectrum ◽  
Route Of Administration ◽  
Intravenous Route ◽  
The Stability

While remdesivir remains one of the few drugs approved by the FDA to treat coronavirus disease 2019 (COVID-19), its intravenous route of administration limits its use to hospital settings. Optimizing the stability and absorption of remdesivir may lead to a more accessible and clinically potent therapeutic.

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 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 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 Antifungal Activity of Gepinacin Scaffold Glycosylphosphatidylinositol Anchor Biosynthesis Inhibitors with Improved Metabolic Stability

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Sean D. Liston ◽  
Luke Whitesell ◽  
Catherine A. McLellan ◽  
Ralph Mazitschek ◽  
Vidmantas Petraitis ◽  
...  
Keyword(s):  
Single Dose ◽  
Antifungal Activity ◽  
Broad Spectrum ◽  
Rabbit Model ◽  
Glycosylphosphatidylinositol Anchor ◽  
Structure Activity ◽  
Biosynthesis Inhibitors ◽  
The Stability ◽  
Mammalian Toxicity

ABSTRACT The glycosylphosphatidylinositol anchor biosynthesis inhibitor gepinacin demonstrates broad-spectrum antifungal activity and negligible mammalian toxicity in culture but is metabolically labile. The stability and bioactivity of 39 analogs were tested in vitro to identify LCUT-8, a stabilized lead with increased potency and promising single-dose pharmacokinetics. Unfortunately, no antifungal activity was seen at the maximum dosing achievable in a neutropenic rabbit model. Nevertheless, structure-activity relationships identified here suggest strategies to further improve compound potency, solubility, and stability.

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 Tilorone: A Broad-Spectrum Antiviral For Emerging Viruses

2020 ◽  
Author(s):  
Sean Ekins ◽  
Peter Madrid
Keyword(s):  
Antiviral Activity ◽  
Broad Spectrum ◽  
Chikungunya Virus ◽  
Middle Eastern ◽  
Emerging Viruses

Tilorone demonstrates in vitro antiviral activity against Chikungunya virus (CHIK) and Middle Eastern Respiratory Syndrome Coronavirus (MERS-CoV).

The assessment of the broad spectrum in vitro antiviral activity of a series of organogermanium compounds

1991 ◽  
Vol 15 ◽  
pp. 74
Author(s):  
R.C. Taylor ◽  
S.G. Ward ◽  
N. Kakimoto ◽  
J. Balzarini ◽  
E. De Clercq
Keyword(s):  
Antiviral Activity ◽  
Broad Spectrum ◽  
Organogermanium Compounds

Aryl-Substituted and Benzo-Annulated CycloSal-Derivatives of 2′,3′-Dideoxy-2′,3′-Didehydrothymidine Monophosphate — Correlation of Structure, Hydrolysis Properties and Anti-HIV Activity

2002 ◽  
Vol 13 (2) ◽  
pp. 129-141 ◽  
Author(s):  
Christian Ducho ◽  
Jan Balzarini ◽  
Lieve Naesens ◽  
Erik De Clercq ◽  
Chris Meier
Keyword(s):  
Antiviral Activity ◽  
Degradation Products ◽  
Hydrolytic Stability ◽  
Substitution Pattern ◽  
Cell Extracts ◽  
Hydrolysis Process ◽  
The Stability ◽  
Anti Hiv

The synthesis of phenyl-substituted and benzo-annulated cycloSal phosphate triesters of the nucleoside analogue 2′,3′-dideoxy-2′,3′-didehydrothymidine (d4T, Zerit™) as lipophilic, membrane-soluble pronucleotides is described. The cycloSal moiety was introduced by using cyclic chlorophosphite agents prepared from phenyl-substituted saligenin derivatives and orthohydroxymethylated naphthols, respectively. Hydrolysis studies (HPLC analysis) of the triesters 2, 3 showed a range of hydrolytic stability from 1.4 h up to 5.1 h and the stability could be correlated with the substitution pattern in the cycloSal moiety. A slight decrease of their stability was observed, if phenyl-substituted derivatives were hydrolyzed in human CEM/O cell extracts. D4T and thymine, possible products of enzymatic cleavage of the pronucleotides, were not detected in the cell extracts. A further investigation of the hydrolysis process was performed by 31P-NMR spectroscopy. This technique allowed a precise monitoring of the degradation products and the exact determination of the product ratio. Finally, the newly synthesized compounds were tested concerning their antiviral activity against HIV in vitro. A strong correlation of the hydrolysis properties and the antiviral activity was found. 3-phenyl- cycloSal-d4TMP showed a threefold increase in its anti-HIV-1 activity and retained full activity in thymidine kinase (TK) deficient cells, indicative of a successful TK-bypass.

scholarly journals Ribavirin shows antiviral activity against SARS-CoV-2 and downregulates the activity of TMPRSS2 and the expression of ACE2 in vitro

2021 ◽  
pp. 1-12 ◽  
Author(s):  
Mehmet Altay Unal ◽  
Ceylan Verda Bitirim ◽  
Gokce Yagmur Summak ◽  
Sidar Bereketoglu ◽  
Inci Cevher Zeytin ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Broad Spectrum ◽  
In Silico ◽  
Antiviral Drug ◽  
In Silico Analysis ◽  
Cell Types ◽  
Suppressive Effect ◽  
Inhibitory Effect ◽  
Molecular Techniques

Ribavirin is a guanosine analog with broad-spectrum antiviral activity against RNA viruses. Based on this, we aimed to show the anti-SARS-CoV-2 activity of this drug molecule via in vitro, in silico, and molecular techniques. Ribavirin showed antiviral activity in Vero E6 cells following SARS-CoV-2 infection, whereas the drug itself did not show any toxic effect over the concentration range tested. In silico analysis suggested that ribavirin has a broad-spectrum impact on SARS-CoV-2, acting at different viral proteins. According to the detailed molecular techniques, ribavirin was shown to decrease the expression of TMPRSS2 at both mRNA and protein levels 48 h after treatment. The suppressive effect of ribavirin in ACE2 protein expression was shown to be dependent on cell types. Finally, proteolytic activity assays showed that ribavirin also showed an inhibitory effect on the TMPRSS2 enzyme. Based on these results, we hypothesized that ribavirin may inhibit the expression of TMPRSS2 by modulating the formation of inhibitory G-quadruplex structures at the TMPRSS2 promoter. As a conclusion, ribavirin is a potential antiviral drug for the treatment against SARS-CoV-2, and it interferes with the effects of TMPRSS2 and ACE2 expression.

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