Tryptophan Trimers and Tetramers Inhibit Dengue and Zika Virus Replication by Interfering with Viral Attachment Processes

ABSTRACT Here, we report a class of tryptophan trimers and tetramers that inhibit (at low micromolar range) dengue and Zika virus infection in vitro. These compounds (AL family) have three or four peripheral tryptophan moieties directly linked to a central scaffold through their amino groups; thus, their carboxylic acid groups are free and exposed to the periphery. Structure-activity relationship (SAR) studies demonstrated that the presence of extra phenyl rings with substituents other than COOH at the N1 or C2 position of the indole side chain is a requisite for the antiviral activity against both viruses. The molecules showed potent antiviral activity, with low cytotoxicity, when evaluated on different cell lines. Moreover, they were active against laboratory and clinical strains of all four serotypes of dengue virus as well as a selected group of Zika virus strains. Additional mechanistic studies performed with the two most potent compounds (AL439 and AL440) demonstrated an interaction with the viral envelope glycoprotein (domain III) of dengue 2 virus, preventing virus attachment to the host cell membrane. Since no antiviral agent is approved at the moment against these two flaviviruses, further pharmacokinetic studies with these molecules are needed for their development as future therapeutic/prophylactic drugs.

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Antiviral activity of lambda-carrageenan against influenza viruses in mice and severe acute respiratory syndrome coronavirus 2 in vitro

10.1101/2020.08.23.255364 ◽

2020 ◽

Author(s):

Yejin Jang ◽

Heegwon Shin ◽

Myoung Kyu Lee ◽

Oh Seung Kwon ◽

Jin Soo Shin ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Antiviral Activity ◽

Influenza A ◽

Antiviral Agent ◽

Influenza Viruses ◽

Host Cells ◽

Progeny Virus ◽

Dependent Manner ◽

Viral Attachment

ABSTRACTInfluenza virus and coronavirus, belonging to enveloped RNA viruses, are major causes of human respiratory diseases. The aim of this study was to investigate the broad spectrum antiviral activity of a naturally existing sulfated polysaccharide, lambda-carrageenan (λ-CGN), purified from marine red algae. Cell culture-based assays revealed that the macromolecule efficiently inhibited both influenza A and B viruses, as well as currently circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with EC50 values ranging from 0.3–1.4 μg/ml. No toxicity to host cells was observed at concentrations up to 300 μg/ml. Plaque titration and western blot analysis verified that λ-CGN reduced expression of viral proteins in cell lysates and suppressed progeny virus production in culture supernatants in a dose-dependent manner. This polyanionic compound exerts antiviral activity by targeting viral attachment to cell surface receptors and preventing entry. Moreover, intranasal administration to mice during influenza A viral challenge not only alleviated infection-mediated reductions in body weight but also protected 60% of mice from virus-induced mortality. Thus, λ-CGN could be a promising antiviral agent for preventing infection by several respiratory viruses.

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Filociclovir Is an Active Antiviral Agent against Ocular Adenovirus Isolates In Vitro and in the Ad5/NZW Rabbit Ocular Model

Pharmaceuticals ◽

10.3390/ph14040294 ◽

2021 ◽

Vol 14 (4) ◽

pp. 294

Author(s):

Eric G. Romanowski ◽

Islam T. M. Hussein ◽

Steven C. Cardinale ◽

Michelle M. Butler ◽

Lucas R. Morin ◽

...

Keyword(s):

Antiviral Activity ◽

Topical Treatment ◽

Antiviral Agent ◽

Human Adenovirus ◽

Treatment Groups ◽

Ocular Infections ◽

The Mean ◽

Eye Infection

Presently, there is no FDA- or EMA-approved antiviral for the treatment of human adenovirus (HAdV) ocular infections. This study determined the antiviral activity of filociclovir (FCV) against ocular HAdV isolates in vitro and in the Ad5/NZW rabbit ocular model. The 50% effective concentrations (EC50) of FCV and cidofovir (CDV) were determined for several ocular HAdV types using standard plaque reduction assays. Rabbits were topically inoculated in both eyes with HAdV5. On day 1, the rabbits were divided into four topical treatment groups: (1) 0.5% FCV 4x/day × 10 d; (2) 0.1% FCV 4x/day × 10 d; (3) 0.5% CDV 2x/day × 7 d; (4) vehicle 4x/day × 10 d. Eyes were cultured for virus on days 0, 1, 3, 4, 5, 7, 9, 11, and 14. The resulting viral eye titers were determined using standard plaque assays. The mean in vitro EC50 for FCV against tested HAdV types ranged from 0.50 to 4.68 µM, whereas those treated with CDV ranged from 0.49 to 30.3 µM. In vivo, compared to vehicle, 0.5% FCV, 0.1% FCV, and 0.5% CDV produced lower eye titers, fewer numbers of positive eye cultures, and shorter durations of eye infection. FCV demonstrated anti-adenovirus activity in vitro and in vivo.

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Improving the Solubilization and Bioavailability of Arbidol Hydrochloride by the Preparation of Binary and Ternary β-Cyclodextrin Complexes with Poloxamer 188

Pharmaceuticals ◽

10.3390/ph14050411 ◽

2021 ◽

Vol 14 (5) ◽

pp. 411

Author(s):

Md. Khalid Anwer ◽

Muzaffar Iqbal ◽

Mohammad Muqtader Ahmed ◽

Mohammed F. Aldawsari ◽

Mohd Nazam Ansari ◽

...

Keyword(s):

Antiviral Agent ◽

Aqueous Solubility ◽

Phase Solubility ◽

Pharmacokinetic Studies ◽

Solubility Curve ◽

Cyclodextrin Complexes ◽

Poloxamer 188 ◽

The Stability

In the current study, the effect of poloxamer 188 on the complexation efficiency and dissolution of arbidol hydrochloride (ADL), a broad-spectrum antiviral agent, with β-cyclodextrin (β-CD) was investigated. Phase solubility studies confirmed a stoichiometry of a 1:1 ratio for both ADL:β-CD and ADL/β-CD with a 1% poloxamer 188 system with an AL type of phase solubility curve. The stability constants (K1:1) calculated from the AL type diagram were 550 M-1 and 2134 M-1 for AD:β-CD and ADL/β-CD with 1% poloxamer 188, respectively. The binary ADL/β-CD and ternary ADL/β-CD with 1% poloxamer 188 complexes were prepared by kneading and a solvent evaporation method and were characterized by aqueous solubility, FTIR, PXRD, DSC and SEM in vitro studies. The solubility (13.1 fold) and release of ADL were markedly improved in kneaded ternary ADL/β-CD with 1% poloxamer 188 (KDB). The binding affinity of ADL and β-CD was confirmed by 1H NMR and 2D ROSEY studies. The ternary complex (KDB) was further subjected for in vivo pharmacokinetic studies in rats and a significant improvement in the bioavailability (2.17 fold) was observed in comparison with pure ADL. Therefore, it can be concluded that the solubilization and bioavailability of ADL can be remarkably increased by ADL/β-CD complexation in the presence of a third component, poloxamer 188.

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Pharmacology and Pharmacokinetics of the Antiviral Agent β-d-2′,3′-Dideoxy-3′-Oxa-5-Fluorocytidine in Cells and Rhesus Monkeys

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.7.2589-2597.2005 ◽

2005 ◽

Vol 49 (7) ◽

pp. 2589-2597 ◽

Cited By ~ 6

Author(s):

Brenda I. Hernandez-Santiago ◽

Huachun Chen ◽

Ghazia Asif ◽

Thierry Beltran ◽

Shuli Mao ◽

...

Keyword(s):

Rhesus Monkeys ◽

Human Peripheral Blood ◽

Antiviral Agent ◽

Pharmacokinetic Studies ◽

Peripheral Blood Mononuclear ◽

Cell Extracts ◽

Human T Cell ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT β-d-2′,3′-Dideoxy-3′-oxa-5-fluorocytidine (d-FDOC) is an effective inhibitor of human immunodeficiency virus 1 (HIV-1) and HIV-2, simian immunodeficiency virus, and hepatitis B virus (HBV) in vitro. The purpose of this study was to evaluate the intracellular metabolism of d-FDOC in human hepatoma (HepG2), human T-cell lymphoma (CEM), and primary human peripheral blood mononuclear (PBM) cells by using tritiated compound. By 24 h, the levels of d-FDOC-triphosphate (d-FDOC-TP) were 2.8 ± 0.4, 6.7 ± 2.3, and 2.0 ± 0.1 pmol/106 cells in HepG2, CEM, and primary human PBM cells, respectively. Intracellular d-FDOC-TP concentrations remained greater than the 50% inhibitory concentration for HIV-1 reverse transcriptase for up to 24 h after removal of the drug from cell cultures. In addition to d-FDOC-monophosphate (d-FDOC-MP), -diphosphate (d-FDOC-DP), and -TP, d-FDOC-DP-ethanolamine and d-FDOC-DP-choline were detected in all cell extracts as major intracellular metabolites. d-FDOC was not a substrate for Escherichia coli thymidine phosphorylase. No toxicity was observed in mice given d-FDOC intraperitoneally for 6 days up to a dose of 100 mg/kg per day. Pharmacokinetic studies in rhesus monkeys indicated that d-FDOC has a t 1/2 of 2.1 h in plasma and an oral bioavailability of 38%. The nucleoside was excreted unchanged primary in the urine, and no metabolites were detected in plasma or urine. These results suggest that further safety and pharmacological studies are warranted to assess the potential of this nucleoside for the treatment of HIV- and HBV-infected individuals.

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In Vitro Inhibition of Zika Virus Replication with Amantadine and Rimantadine Hydrochlorides

Microbiology Research ◽

10.3390/microbiolres12030052 ◽

2021 ◽

Vol 12 (3) ◽

pp. 727-738

Author(s):

Jorge L. Arias-Arias ◽

Francisco Vega-Aguilar ◽

Dihalá Picado-Soto ◽

Eugenia Corrales-Aguilar ◽

Gilbert D. Loría

Keyword(s):

Antiviral Activity ◽

Zika Virus ◽

Influenza A ◽

Yellow Fever Virus ◽

Human Infection ◽

Virus Infections ◽

Drug Concentrations ◽

Dose Dependent ◽

Reference Strains

Zika virus (ZIKV) is a mosquito-borne flavivirus in which human infection became relevant during recent outbreaks in Latin America due to its unrecognized association with fetal neurological disorders. Currently, there are no approved effective antivirals or vaccines for the treatment or prevention of ZIKV infections. Amantadine and rimantadine are approved antivirals used against susceptible influenza A virus infections that have been shown to have antiviral activity against other viruses, such as dengue virus (DENV). Here, we report the in vitro effectiveness of both amantadine and rimantadine hydrochlorides against ZIKV replication, resulting in a dose-dependent reduction in viral titers of a ZIKV clinical isolate and two different ZIKV reference strains. Additionally, we demonstrate similar in vitro antiviral activity of these drugs against DENV-1 and yellow fever virus (YFV), although at higher drug concentrations for the latter. ZIKV replication was inhibited at drug concentrations well below cytotoxic levels of both compounds, as denoted by the high selectivity indexes obtained with the tested strains. Further work is absolutely needed to determine the potential clinical use of these antivirals against ZIKV infections, but our results suggest the existence of a highly conserved mechanism across flavivirus, susceptible to be blocked by modified more specific adamantane compounds.

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Astodrimer sodium, dendrimer antiviral, inhibits replication of SARS-CoV-2 in vitro

10.1101/2020.08.20.260190 ◽

2020 ◽

Cited By ~ 1

Author(s):

Jeremy R.A. Paull ◽

Alex Castellarnau ◽

Carolyn A. Luscombe ◽

Jacinth K. Fairley ◽

Graham P. Heery

Keyword(s):

Antiviral Activity ◽

Host Cell ◽

Cytopathic Effect ◽

Limit Of Detection ◽

Antiviral Agent ◽

Effective Response ◽

Enveloped Viruses ◽

Host Cell Interactions

AbstractAn effective response to the ongoing coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will require a range of complementary preventive modalities. The current studies were conducted to evaluate the in vitro SARS-CoV-2 antiviral activity of astodrimer sodium, a dendrimer with broad spectrum antimicrobial activity, including against enveloped viruses in in vitro and in vivo models, that is marketed for antiviral and antibacterial applications. We report that astodrimer sodium inhibits replication of SARS-CoV-2 in Vero E6 cells when added to cells 1-hour prior to or 1-hour post infection, with 50% effective concentrations reducing virus-induced cytopathic effect (EC50) ranging from 0.090 to 0.742 μM (0.002 to 0.012 mg/mL). The selectivity index (SI) in these assays was as high as 2197. Astodrimer sodium was also effective in a virucidal evaluation when mixed with virus for 1 hour prior to infection of cells (EC50 1.83 μM [0.030 mg/mL]). Results from a time of addition study, which showed infectious virus was below the lower limit of detection at all time points tested, were consistent with the compound inhibiting early virus entry steps. The data were similar for all investigations and were consistent with the potent antiviral activity of astodrimer sodium being due to inhibition of virus-host cell interactions, as previously demonstrated for other viruses. Further studies will confirm if astodrimer sodium binds to SARS-CoV-2 spike protein and physically blocks initial association of the virus with heparan sulfate proteoglycans on the host cell. Given the in vitro effectiveness and significantly high SI, astodrimer sodium warrants further investigation for potential as a nasally administered or inhaled antiviral agent for SARS-CoV-2 prevention and treatment applications.

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In vitro antiviral activity against Zika virus from a natural product of the Brazilian red seaweed Bryothamnion triquetrum

Acta Virologica ◽

10.4149/av_2021_406 ◽

2021 ◽

Author(s):

Claudio C. Cirne-Santos ◽

Caroline de ◽

Vitor W. Rabelo ◽

Priscilla O. ◽

Max W. L. ◽

...

Keyword(s):

Antiviral Activity ◽

Natural Product ◽

Zika Virus ◽

Red Seaweed

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Antiviral Activity ofIsatis indigoticaExtract and Its Derived Indirubin against Japanese Encephalitis Virus

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/925830 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 18

Author(s):

Shu-Jen Chang ◽

Yi-Chih Chang ◽

Kai-Zen Lu ◽

Yi-Yun Tsou ◽

Cheng-Wen Lin

Keyword(s):

Antiviral Activity ◽

Japanese Encephalitis Virus ◽

Japanese Encephalitis ◽

Antiviral Effect ◽

Inhibitory Effect ◽

Encephalitis Virus ◽

Simultaneous Treatment ◽

Virus Attachment ◽

Antiviral Activities

Isatis indigoticais widely used in Chinese Traditional Medicine for clinical treatment of virus infection, tumor, and inflammation, yet its antiviral activities remain unclear. This study probed antiviral activity ofI. indigoticaextract and its marker compounds against Japanese encephalitis virus (JEV).I. indigoticamethanol extract, indigo, and indirubin proved less cytotoxic than other components, showing inhibitory effect (concentration-dependent) on JEV replicationin vitro. Time-of-addition experiments proved the extract, indigo, and indirubin with potent antiviral effect by pretreatment (before infection) or simultaneous treatment (during infection), but not posttreatment (after entry). Antiviral action of these agents showed correlation with blocking virus attachment and exhibited potent virucidal activity. In particular, indirubin had strong protective ability in a mouse model with lethal JEV challenge. The study could yield anti-JEV agents.

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Papaya Fruit Pulp and Resulting Lactic Fermented Pulp Exert Antiviral Activity against Zika Virus

Microorganisms ◽

10.3390/microorganisms8091257 ◽

2020 ◽

Vol 8 (9) ◽

pp. 1257

Author(s):

Juliano G. Haddad ◽

Victoria Carcauzon ◽

Omar El Kalamouni ◽

Philippe Desprès ◽

Cyrielle Garcia ◽

...

Keyword(s):

Antiviral Activity ◽

Zika Virus ◽

Human Cells ◽

Host Cells ◽

Dependent Manner ◽

Bacterial Strains ◽

Lactic Fermentation ◽

Papaya Pulp ◽

Leuconostoc Pseudomesenteroides

There are a several emerging and re-emerging RNA viruses that are prevalent around the world for which there are no licensed vaccines or antiviral drugs. Zika virus (ZIKV) is an example of an emerging virus that has become a significant concern worldwide because of its association with severe congenital malformations and neurological disorders in adults. Several polyphenol-rich extracts from plants were used as nutraceuticals which exhibit potent in vitro antiviral effects. Here, we demonstrated that the papaya pulp extracted from Carica papaya fruit inhibits the infection of ZIKV in human cells without loss of cell viability. At the non-cytotoxic concentrations, papaya pulp extract has the ability to reduce the virus progeny production in ZIKV-infected human cells by at least 4-log, regardless of viral strains tested. Time-of-drug-addition assays revealed that papaya pulp extract interfered with the attachment of viral particles to the host cells. With a view of preserving the properties of papaya pulp over time, lactic fermentation based on the use of bacterial strains Weissella cibaria 64, Lactobacillus plantarum 75 and Leuconostoc pseudomesenteroides 56 was performed and the resulting fermented papaya pulp samples were tested on ZIKV. We found that lactic fermentation of papaya pulp causes a moderate loss of antiviral activity against ZIKV in a bacterial strain-dependent manner. Whereas IC50 of the papaya pulp extract was 0.3 mg/mL, we found that fermentation resulted in IC50 up to 4 mg/mL. We can conclude that papaya pulp possesses antiviral activity against ZIKV and the fermentation process has a moderate effect on the antiviral effect.

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Adenosine Analog NITD008 Is a Potent Inhibitor of Zika Virus

Open Forum Infectious Diseases ◽

10.1093/ofid/ofw175 ◽

2016 ◽

Vol 3 (4) ◽

Cited By ~ 85

Author(s):

Yong-Qiang Deng ◽

Na-Na Zhang ◽

Chun-Feng Li ◽

Min Tian ◽

Jia-Nan Hao ◽

...

Keyword(s):

Antiviral Activity ◽

Zika Virus ◽

Potent Inhibitor ◽

Antiviral Drug ◽

Clinical Manifestations ◽

Drug Screen ◽

Adenosine Analog

Abstract The ongoing Zika virus (ZIKV) outbreaks have raised global concerns due to its unexpected clinical manifestations. Antiviral development is of high priority in response to the ZIKV emergency. In this study, we report that an adenosine analog NITD008 has potent in vitro and in vivo antiviral activity against ZIKV. The compound can effectively inhibit the historical and contemporary ZIKV strains in cultures as well as significantly reduce viremia and prevent mortality in A129 mice. Our results have demonstrated that NITD008 is potent inhibitor of ZIKV and can be used as reference inhibitor for future ZIKV antiviral drug screen and discovery.

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