The Bioactive Lipid 4-Hydroxyphenyl Retinamide Inhibits Flavivirus Replication

ABSTRACTDengue virus (DENV), a member of theFlaviviridaefamily, is a mosquito-borne pathogen and the cause of dengue fever. The increasing prevalence of DENV worldwide heightens the need for an effective vaccine and specific antivirals. Due to the dependence of DENV upon the lipid biosynthetic machinery of the host cell, lipid signaling and metabolism present unique opportunities for inhibiting viral replication. We screened a library of bioactive lipids and modulators of lipid metabolism and identified 4-hydroxyphenyl retinamide (4-HPR) (fenretinide) as an inhibitor of DENV in cell culture. 4-HPR inhibits the steady-state accumulation of viral genomic RNA and reduces viremia when orally administered in a murine model of DENV infection. The molecular target responsible for this antiviral activity is distinct from other known inhibitors of DENV but appears to affect other members of theFlaviviridae, including the West Nile, Modoc, and hepatitis C viruses. Although long-chain ceramides have been implicated in DENV replication, we demonstrate that DENV is insensitive to the perturbation of long-chain ceramides in mammalian cell culture and that the effect of 4-HPR on dihydroceramide homeostasis is separable from its antiviral activity. Likewise, the induction of reactive oxygen species by 4-HPR is not required for the inhibition of DENV. The inhibition of DENVin vivoby 4-HPR, combined with its well-established safety and tolerability in humans, suggests that it may be repurposed as a pan-Flaviviridaeantiviral agent. This work also illustrates the utility of bioactive lipid screens for identifying critical interactions of DENV and other viral pathogens with host lipid biosynthesis, metabolism, and signal transduction.

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The antiviral effect of metformin on zika and dengue virus infection

Scientific Reports ◽

10.1038/s41598-021-87707-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Carlos Noe Farfan-Morales ◽

Carlos Daniel Cordero-Rivera ◽

Juan Fidel Osuna-Ramos ◽

Irma Eloisa Monroy-Muñoz ◽

Luis Adrián De Jesús-González ◽

...

Keyword(s):

Yellow Fever Virus ◽

Antiviral Agent ◽

Denv Infection ◽

Health Concern ◽

Effective Vaccine ◽

In Vivo Model ◽

Zikv Infection ◽

Immunodeficient Mice

AbstractThe Dengue (DENV) and zika (ZIKV) virus infections are currently a public health concern. At present, there is no treatment or a safe and effective vaccine for these viruses. Hence, the development of new strategies as host-directed therapy is required. In this sense, Metformin (MET), an FDA-approved drug used for the treatment of type 2 diabetes, has shown an anti-DENV effect in vitro by activating AMPK and reducing HMGCR activity. In this study, MET treatment was evaluated during in vitro and in vivo ZIKV infection and compared to MET treatment during DENV infection. Our results demonstrated that MET has a broad in vitro antiviral spectrum. MET inhibited ZIKV infection in different cell lines, but it was most effective in inhibiting DENV and yellow fever virus (YFV) infection in Huh-7 cells. However, the drug failed to protect against ZIKV infection when AG129 immunodeficient mice were used as in vivo model. Interestingly, MET increased DENV-infected male mice's survival time, reducing the severe signs of the disease. Together, these findings indicate that, although MET was an effective antiviral agent to inhibit in vitro and in vivo DENV infection, it could only inhibit in vitro ZIKV infection.

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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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Albumin Enhances Caspofungin Activity against Aspergillus Species by Facilitating Drug Delivery to Germinating Hyphae

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02026-15 ◽

2015 ◽

Vol 60 (3) ◽

pp. 1226-1233 ◽

Cited By ~ 3

Author(s):

Petros Ioannou ◽

Aggeliki Andrianaki ◽

Tonia Akoumianaki ◽

Irene Kyrmizi ◽

Nathaniel Albert ◽

...

Keyword(s):

Drug Delivery ◽

Cell Culture ◽

Antifungal Agents ◽

Fold Increase ◽

Culture Conditions ◽

The Other ◽

Related Factors ◽

Content Type

The modestin vitroactivity of echinocandins againstAspergillusimplies that host-related factors augment the action of these antifungal agentsin vivo. We found that, in contrast to the other antifungal agents (voriconazole, amphotericin B) tested, caspofungin exhibited a profound increase in activity against variousAspergillusspecies under conditions of cell culture growth, as evidenced by a ≥4-fold decrease in minimum effective concentrations (MECs) (P= 0. 0005). Importantly, the enhanced activity of caspofungin againstAspergillusspp. under cell culture conditions was strictly dependent on serum albumin and was not observed with the other two echinocandins, micafungin and anidulafungin. Of interest, fluorescently labeled albumin bound preferentially on the surface of germinatingAspergillushyphae, and this interaction was further enhanced upon treatment with caspofungin. In addition, supplementation of cell culture medium with albumin resulted in a significant, 5-fold increase in association of fluorescently labeled caspofungin withAspergillushyphae (P< 0.0001). Collectively, we found a novel synergistic interaction between albumin and caspofungin, with albumin acting as a potential carrier molecule to facilitate antifungal drug delivery toAspergillushyphae.

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In vitro activity of human recombinant alpha-2b interferon against SARS-CoV-2 virus

Voprosy Virusologii ◽

10.36233/0507-4088-13 ◽

2021 ◽

Vol 66 (2) ◽

pp. 123-128

Author(s):

S. Ya. Loginova ◽

V. N. Shсhukina ◽

S. V. Savenko ◽

S. V. Borisevich

Keyword(s):

Cell Culture ◽

Antiviral Activity ◽

Viral Infections ◽

Complete Suppression ◽

Antiviral Efficacy ◽

Prevention And Treatment ◽

Proven Efficacy ◽

High Antiviral Activity

Introduction. The pandemic spread of a new coronavirus infection, COVID-19, has caused a global emergency and attracted the attention of public health professionals and the population of all countries. A significant increase in the number of new cases of SARS-CoV-2 infection demonstrates the urgency of finding drugs effective against this pathogen.The aim of this work was to evaluate the in vitro antiviral efficacy of human recombinant alpha-2b interferon (IFN-α2b) against SARS-CoV-2 virus.Material and methods. The experiments had been carried out on Vero Cl008, the continuous line of African green monkey (Chlorocebus sabaeus) kidney cells. The effectiveness of the drugs was assessed by the suppression of viral reproduction in vitro. The biological activity was determined using titration of a virus-containing suspension in a Vero Cl008 cell culture by the formation of negative colonies.Results. The antiviral efficacy of the IFN-α2b-based medications, which have a high safety profile and proven efficacy in the prevention and treatment of influenza and acute respiratory viral infections (ARVI), has been studied against the new pandemic SARS-CoV-2 virus in vitro experiments in Vero C1008 cell culture. IFN-α2b effectively inhibits the reproduction of the virus when applied both 24 hrs before and 2 hrs after infection. In the IFN-α2b concentration range 102–106 IU/ml a complete suppression of the reproduction of the SARS-CoV-2 virus had been demonstrated.Discussion. IFN-α2b demonstrated in vitro high antiviral activity against SARS-CoV-2. In addition, the substance has a high chemotherapeutic index (>1000).Conclusion. Medications for intranasal use based on IFN-α2b have high antiviral activity and are promising drugs for in vivo study in terms of prevention and treatment of COVID-19.

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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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Preclinical Efficacy of a Lipooligosaccharide Peptide Mimic Candidate Gonococcal Vaccine

mBio ◽

10.1128/mbio.02552-19 ◽

2019 ◽

Vol 10 (6) ◽

Cited By ~ 3

Author(s):

Sunita Gulati ◽

Michael W. Pennington ◽

Andrzej Czerwinski ◽

Darrick Carter ◽

Bo Zheng ◽

...

Keyword(s):

Monoclonal Antibody ◽

Neisseria Gonorrhoeae ◽

Vaccine Candidate ◽

Peptide Vaccine ◽

Human Infection ◽

Effective Vaccine ◽

Infection Model ◽

Content Type ◽

Peptide Mimic

ABSTRACT The global spread of multidrug-resistant strains of Neisseria gonorrhoeae constitutes a public health emergency. With limited antibiotic treatment options, there is an urgent need for development of a safe and effective vaccine against gonorrhea. Previously, we constructed a prototype vaccine candidate comprising a peptide mimic (mimitope) of a glycan epitope on gonococcal lipooligosaccharide (LOS), recognized by monoclonal antibody 2C7. The 2C7 epitope is (i) broadly expressed as a gonococcal antigenic target in human infection, (ii) a critical requirement for gonococcal colonization in the experimental setting, and (iii) a virulence determinant that is maintained and expressed by gonococci. Here, we have synthesized to >95% purity through a relatively facile and economical process a tetrapeptide derivative of the mimitope that was cyclized through a nonreducible thioether bond, thereby rendering the compound homogeneous and stable. This vaccine candidate, called TMCP2, when administered at 0, 3, and 6 weeks to BALB/c mice at either 50, 100 or 200 μg/dose in combination with glucopyranosyl lipid A-stable oil-in-water nanoemulsion (GLA-SE; a Toll-like receptor 4 and TH1-promoting adjuvant), elicited bactericidal IgG and reduced colonization levels of gonococci in experimentally infected mice while accelerating clearance by each of two different gonococcal strains. Similarly, a 3-dose biweekly schedule (50 μg TMCP2/dose) was also effective in mice. We have developed a gonococcal vaccine candidate that can be scaled up and produced economically to a high degree of purity. The candidate elicits bactericidal antibodies and is efficacious in a preclinical experimental infection model. IMPORTANCE Neisseria gonorrhoeae has become resistant to most antibiotics. The incidence of gonorrhea is also sharply increasing. A safe and effective antigonococcal vaccine is urgently needed. Lipooligosaccharide (LOS), the most abundant outer membrane molecule, is indispensable for gonococcal pathogenesis. A glycan epitope on LOS that is recognized by monoclonal antibody (MAb) 2C7 (called the 2C7 epitope) is expressed almost universally by gonococci in vivo. Previously, we identified a peptide mimic (mimitope) of the 2C7 epitope, which when configured as an octamer and used as an immunogen, attenuated colonization of mice by gonococci. Here, a homogenous, stable tetrameric derivative of the mimitope, when combined with a TH1-promoting adjuvant and used as an immunogen, also effectively attenuates gonococcal colonization of mice. This candidate peptide vaccine can be produced economically, an important consideration for gonorrhea, which affects socioeconomically underprivileged populations disproportionately, and represents an important advance in the development of a gonorrhea vaccine.

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T-705 (Favipiravir) Inhibition of Arenavirus Replication in Cell Culture

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01219-10 ◽

2010 ◽

Vol 55 (2) ◽

pp. 782-787 ◽

Cited By ~ 67

Author(s):

Michelle Mendenhall ◽

Andrew Russell ◽

Terry Juelich ◽

Emily L. Messina ◽

Donald F. Smee ◽

...

Keyword(s):

Cell Culture ◽

Antiviral Activity ◽

Viral Replication ◽

Antiviral Agent ◽

Febrile Illness ◽

Hemorrhagic Fever ◽

Intermediate Stage ◽

Lymphocytic Choriomeningitis ◽

Hamster Model ◽

Highly Pathogenic

ABSTRACTA number of New World arenaviruses (Junín [JUNV], Machupo [MACV], and Guanarito [GTOV] viruses) can cause human disease ranging from mild febrile illness to a severe and often fatal hemorrhagic fever syndrome. These highly pathogenic viruses and the Old World Lassa fever virus pose a significant threat to public health and national security. The only licensed antiviral agent with activity against these viruses, ribavirin, has had mixed success in treating severe arenaviral disease and is associated with significant toxicities. A novel pyrazine derivative currently in clinical trials for the treatment of influenza virus infections, T-705 (favipiravir), has demonstrated broad-spectrum activity against a number of RNA viruses, including arenaviruses. T-705 has also been shown to be effective against Pichinde arenavirus infection in a hamster model. Here, we demonstrate the robust antiviral activity of T-705 against authentic highly pathogenic arenaviruses in cell culture. We show that T-705 disrupts an early or intermediate stage in viral replication, distinct from absorption or release, and that its antiviral activity in cell culture is reversed by the addition of purine bases and nucleosides, but not with pyrimidines. Specific inhibition of viral replication/transcription by T-705 was demonstrated using a lymphocytic choriomeningitis arenavirus replicon system. Our findings indicate that T-705 acts to inhibit arenavirus replication/transcription and may directly target the viral RNA-dependent RNA polymerase.

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Extracellular 2′-5′ Oligoadenylate Synthetase Stimulates RNase L-Independent Antiviral Activity: a Novel Mechanism of Virus-Induced Innate Immunity

Journal of Virology ◽

10.1128/jvi.01003-10 ◽

2010 ◽

Vol 84 (22) ◽

pp. 11898-11904 ◽

Cited By ~ 49

Author(s):

Helle Kristiansen ◽

Christina A. Scherer ◽

Maralee McVean ◽

Shawn P. Iadonato ◽

Susanne Vends ◽

...

Keyword(s):

Antiviral Activity ◽

Antiviral Agent ◽

Rnase L ◽

Oligoadenylate Synthetase ◽

Antiviral Compound ◽

Clinical Prognosis ◽

Strong Antiviral Activity ◽

Infected Cells

ABSTRACT The 2′-5′ oligoadenylate synthetase (OAS) proteins are traditionally considered intracellular antiviral proteins. However, several studies demonstrate a correlation between the concentration of freely circulating OAS protein in sera from hepatitis C patients and their clinical prognosis. Here we demonstrate that extracellular OAS1 enters into cells and possesses a strong antiviral activity, both in vitro and in vivo, which is independent of RNase L. The OAS protein directly inhibits viral proliferation and does not require the activation of known antiviral signaling pathways. We propose that OAS produced by cells infected with viruses is released to the extracellular space, where it acts as a paracrine antiviral agent. Thus, the OAS protein represents the first direct antiviral compound released by virus-infected cells.

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(−)-Epigallocatechin-3-Gallate Inhibits the Life Cycle of Pseudorabies Virus In Vitro and Protects Mice Against Fatal Infection

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2020.616895 ◽

2021 ◽

Vol 10 ◽

Author(s):

Changchao Huan ◽

Weiyin Xu ◽

Tingting Guo ◽

Haochun Pan ◽

Hengyue Zou ◽

...

Keyword(s):

Antiviral Activity ◽

Pseudorabies Virus ◽

Antiviral Agent ◽

Economic Cost ◽

Dependent Manner ◽

Swine Industry ◽

Effective Prevention ◽

Dose Dependent

A newly emerged pseudorabies virus (PRV) variant with enhanced pathogenicity has been identiﬁed in many PRV-vaccinated swine in China since 2011. The PRV variant has caused great economic cost to the swine industry, and measures for the effective prevention and treatment of this PRV variant are still lacking. (–)-Epigallocatechin-3-gallate (EGCG) exhibits antiviral activity against diverse viruses and thus in this study, we investigated the anti-PRV activity of EGCG in vitro and in vivo. EGCG significantly inhibited infectivity of PRV Ra and PRV XJ5 strains in PK15 B6 cells and Vero cells. The anti-PRV activity of EGCG was dose-dependent, and 50 μM EGCG could completely block viral infection at different multiplicities of infection. We next revealed that EGCG blocked PRV adsorption and entry to PK15 B6 cells in a dose-dependent manner, but inhibition of PRV entry by EGCG was not as efficient as its inhibition of PRV adsorption. PRV replication was suppressed in PK15 B6 cells treated with EGCG post-infection. However, EGCG did not affect PRV assembly and could promote PRV release. Furthermore, 40 mg/kg EGCG provided 100% protection in BALB/c mice challenged with PRV XJ5, when EGCG was administrated both pre- and post-challenge. These results revealed that EGCG exhibits antiviral activity against PRV mainly by inhibiting virus adsorption, entry and replication in vitro. Meanwhile, EGCG increased the survival of mice challenged with PRV. Therefore, EGCG might be a potential antiviral agent against PRV infection.

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Nafamostat-interferon-alpha combination suppresses SARS-CoV-2 infection in vitro and in vivo

10.1101/2021.06.16.448653 ◽

2021 ◽

Author(s):

Aleksandr Ianevski ◽

Rouan Yo ◽

Hilde Lysvand ◽

Gunnveig Grodeland ◽

Nicolas Legrand ◽

...

Keyword(s):

Public Health ◽

Patient Outcome ◽

Cell Culture ◽

Antiviral Activity ◽

Critical Role ◽

Low Doses ◽

Important Mediator ◽

The World

SARS-CoV-2 and its vaccine/immune-escaping variants continue to pose a serious threat to public health due to a paucity of effective, rapidly deployable, and widely available treatments. Here we address these challenges by combining Pegasys (IFNa) and nafamostat to effectively suppress SARS-CoV-2 infection in cell culture and hamsters. Our results indicate that Serpin E1 is an important mediator of the antiviral activity of IFNa and that both Serpin E1 and camostat can target the same cellular factor TMPRSS2, which plays a critical role in viral replication. The low doses of the drugs in combination may have several clinical advantages, including fewer adverse events and improved patient outcome. Thus, our study may provide a proactive solution for the ongoing pandemic and potential future coronavirus outbreaks, which is still urgently required in many parts of the world.

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