viral

Daddy-Daughter Duo's Cheerleading Stunts Go Viral



This 4-year-old girl seems fearless.




viral

Detroit Neighbors Go Viral in Social Distancing Dance



Coronavirus can’t stop, won’t stop a Motor City tradition.




viral

Daddy-Daughter Duo's Cheerleading Stunts Go Viral



This 4-year-old girl seems fearless.




viral

Hilarious Review of Patti LaBelle's Pie Goes Viral



"Patti, I have to say, girl, you did it with this pie."




viral

Furry Fandom and the Internet forced back to roots by viral outbreak

The internet was seen as a major catalyst for the furry fandom finding one another during the times before we held conventions. During that earlier period in the 1990s, conventions and meets were rare, and finding one another was done mostly through the chat rooms and message boards of the past. There was no bandwidth for video or sharing major animation projects, therefore most of our intimate conversations were textual.

For many younger furries, it was a time that was lost in the annals of a distant history. Instead they found themselves joining in amongst a wave of growing conventions being held in various places around the world on any given weekend. Ones where those in custom fursuits march out in the streets openly rather than feeling a stifling isolation of being cooped up in hotel spaces, with a handful of home made creations, being wary of a hostile media looking for a freak show.

Coming out of 2019, it seemed that the time where furry was just an internet thing was fully behind it. However a series of unfortunate events were in line for 2020, a year that has led humanity to be forced into their rooms by an irate Mother Nature as an easily spread virus has forced governments around the globe to take drastic measures to slow its spread and put strict limits on social gatherings. A situation which has forced both the furry fandom, and the internet that brought it together, back to their roots.

read more






viral

Impact of antiretroviral therapy on liver disease progression and mortality in patients co-infected with HIV and hepatitis C: systematic review and meta-analysis

Systematic review produced by the EPPI-Centre in 2015.This systematic review aimed to evaluate the effect of HAART and ARV monotherapy on liver disease progression and liver-related mortality in individuals co-infected with HIV and hepatitis C, including in patients with haemophilia.





viral

How Can You Use Viral Marketing Techniques to Get Free Home Business Leads?

So, you are here to learn how you can use viral marketing techniques to get free home business leads! Well great stuff I have a few magical tips for you to achieve just that.




viral

MacMillan, Ploss labs to map viral-host interactions for COVID-19

Responding to a challenge that tragic necessity has thrown to countless research labs around the world, a team from the Department of Chemistry will deploy its new cell mapping technology to shed light on the molecular interplay between COVID-19 and its host. The team is collaborating with Princeton molecular biologists who study viruses.




viral

Is Viral Content Always Successful Content?

It’s an incredibly exciting thing to see something you’ve created go viral. It means people find it so important that they’re sharing it with anyone who’ll listen.
It means you’ll be enjoying an unprecedented influx of traffic, and that both your name and the brand you represent will be – if only for a brief moment – known across the web.
Is that always a good thing, though?
Maybe not. What happens if you go viral for all the wrong ...

The post Is Viral Content Always Successful Content? appeared first on RSS Feed Converter.




viral

Researchers use viral genomes to uncover a Zika outbreak in Cuba

The virus simmered quietly in Cuba for about a year before infecting thousands.




viral

How Christine Baranski pulled off her viral Sondheim song with Streep and McDonald

Christine Baranski explains how she came to sing "The Ladies Who Lunch" with Meryl Streep and Audra McDonald for Stephen Sondheim's virtual birthday.




viral

'Just for the camera?': Jimmy Kimmel deletes viral video that shows Pence delivering empty PPE boxes

Jimmy Kimmel tweeted and deleted a video clip that purportedly showed Vice President Mike Pence delivering empty PPE boxes to a health care center

       




viral

Coronavirus: US authorises use of anti-viral drug Remdesivir

The Food and Drug Administration authorises emergency use of the experimental anti-viral drug.




viral

Podcast: The Power of Viral Stories, with Professor Robert Shiller




viral

The Secretome Profiling of a Pediatric Airway Epithelium Infected with hRSV Identified Aberrant Apical/Basolateral Trafficking and Novel Immune Modulating (CXCL6, CXCL16, CSF3) and Antiviral (CEACAM1) Proteins [Research]

The respiratory epithelium comprises polarized cells at the interface between the environment and airway tissues. Polarized apical and basolateral protein secretions are a feature of airway epithelium homeostasis. Human respiratory syncytial virus (hRSV) is a major human pathogen that primarily targets the respiratory epithelium. However, the consequences of hRSV infection on epithelium secretome polarity and content remain poorly understood. To investigate the hRSV-associated apical and basolateral secretomes, a proteomics approach was combined with an ex vivo pediatric human airway epithelial (HAE) model of hRSV infection (data are available via ProteomeXchange and can be accessed at https://www.ebi.ac.uk/pride/ with identifier PXD013661). Following infection, a skewing of apical/basolateral abundance ratios was identified for several individual proteins. Novel modulators of neutrophil and lymphocyte activation (CXCL6, CSF3, SECTM1 or CXCL16), and antiviral proteins (BST2 or CEACAM1) were detected in infected, but not in uninfected cultures. Importantly, CXCL6, CXCL16, CSF3 were also detected in nasopharyngeal aspirates (NPA) from hRSV-infected infants but not healthy controls. Furthermore, the antiviral activity of CEACAM1 against RSV was confirmed in vitro using BEAS-2B cells. hRSV infection disrupted the polarity of the pediatric respiratory epithelial secretome and was associated with immune modulating proteins (CXCL6, CXCL16, CSF3) never linked with this virus before. In addition, the antiviral activity of CEACAM1 against hRSV had also never been previously characterized. This study, therefore, provides novel insights into RSV pathogenesis and endogenous antiviral responses in pediatric airway epithelium.




viral

The Secretome Profiling of a Pediatric Airway Epithelium Infected with hRSV Identified Aberrant Apical/Basolateral Trafficking and Novel Immune Modulating (CXCL6, CXCL16, CSF3) and Antiviral (CEACAM1) Proteins [Research]

The respiratory epithelium comprises polarized cells at the interface between the environment and airway tissues. Polarized apical and basolateral protein secretions are a feature of airway epithelium homeostasis. Human respiratory syncytial virus (hRSV) is a major human pathogen that primarily targets the respiratory epithelium. However, the consequences of hRSV infection on epithelium secretome polarity and content remain poorly understood. To investigate the hRSV-associated apical and basolateral secretomes, a proteomics approach was combined with an ex vivo pediatric human airway epithelial (HAE) model of hRSV infection (data are available via ProteomeXchange and can be accessed at https://www.ebi.ac.uk/pride/ with identifier PXD013661). Following infection, a skewing of apical/basolateral abundance ratios was identified for several individual proteins. Novel modulators of neutrophil and lymphocyte activation (CXCL6, CSF3, SECTM1 or CXCL16), and antiviral proteins (BST2 or CEACAM1) were detected in infected, but not in uninfected cultures. Importantly, CXCL6, CXCL16, CSF3 were also detected in nasopharyngeal aspirates (NPA) from hRSV-infected infants but not healthy controls. Furthermore, the antiviral activity of CEACAM1 against RSV was confirmed in vitro using BEAS-2B cells. hRSV infection disrupted the polarity of the pediatric respiratory epithelial secretome and was associated with immune modulating proteins (CXCL6, CXCL16, CSF3) never linked with this virus before. In addition, the antiviral activity of CEACAM1 against hRSV had also never been previously characterized. This study, therefore, provides novel insights into RSV pathogenesis and endogenous antiviral responses in pediatric airway epithelium.




viral

Episode 56 - The Internet of Yahoo! (IoY!) Viral sensations and Marissa Mayer

Host Matt Egan leads a three pronged tech attack on the week's news with David Price and Scott Carey. The gang discuss 'BBC Dad' and why the professor's hilarious children are the perfect example of viral video. David Price also examines the news cycle of such treats, and why ambulance drivers aren't on Twitter all the time. With Marissa Mayer leaving Yahoo! in tatters, renamed, but with a wad of cash reportedly in her account, Scott leads the line in exploring where it went wrong and why it has been such a public fall from grace. But at age 41, surely there's another chapter in Mayer's story?  


See acast.com/privacy for privacy and opt-out information.




viral

Re: Reducing risks from coronavirus transmission in the home—the role of viral load




viral

JUTC pulls driver of bus in viral video from active duty

A driver of a Jamaica Urban Transit Company (JUTC) bus has been pulled from active duty following a video showing passengers standing in the vehicle.  A video of the route 75 bus with passengers standing was being circulated on social...




viral

Identifying a viral rash in pregnancy

Viral exanthema can cause rash in a pregnant woman and should be considered even in countries that have comprehensive vaccination programmes. Measles and rubella can cause intrauterine death. Intrauterine infection with rubella can lead to congenital rubella syndrome in the liveborn baby. In this podcast, Jack Carruthers, honorary clinical...




viral

New antivirals for Hepatitis C - what does the evidence prove?

There’s been a lot of attention given to the new antirviral drugs which target Hepatitis C - partly because of the burden of infection of the disease, and the lack of a treatment that can be made easily accessible to around the world, and partly because of the incredible cost of a course of treatment. But a new article on BMJ talks about the...




viral

Use of antiviral drug in poultry is blamed for drug resistant strains of avian flu




viral

Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China, January-March 2020: retrospective cohort study




viral

Teacher's Facebook Post on Students' Social Media Secrets Goes Viral

Utah science teacher Skipper Coates asked her students to complete the following sentence: "What my parents don't know about social media is..."




viral

Hepatitis B virus infection : molecular virology to antiviral drugs

9789811391514 (electronic bk.)




viral

Dynamics of immune activation in viral diseases

9789811510458 (electronic bk.)




viral

Type I Interferons Act Directly on Nociceptors to Produce Pain Sensitization: Implications for Viral Infection-Induced Pain

One of the first signs of viral infection is body-wide aches and pain. Although this type of pain usually subsides, at the extreme, viral infections can induce painful neuropathies that can last for decades. Neither of these types of pain sensitization is well understood. A key part of the response to viral infection is production of interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-β) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I IFNs stimulate MNK-mediated eIF4E phosphorylation in DRG neurons to promote pain hypersensitivity. Endogenous release of type I IFNs with the double-stranded RNA mimetic poly(I:C) likewise produces pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how viral infections promote pain and can lead to neuropathies.

SIGNIFICANCE STATEMENT It is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. Although specific mechanisms have been discovered for diverse bacterial and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type I interferons, one of the first mediators produced by viral infection, act directly on nociceptors to produce pain sensitization. Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling), which is known to produce nociceptor sensitization in inflammatory and neuropathic pain conditions. Our work reveals a mechanism through which viral infections cause heightened pain sensitivity




viral

Miniature Gecko Art Gallery Premieres on the Heels of Viral London Gerbil Museum

The creator behind the reptilian repertoire hopes many more pet museums are in the works




viral

NIH clinical trial evaluates antiviral plus anti-inflammatory drug for COVID-19

A randomized, controlled clinical trial evaluating the safety and efficacy of a treatment regimen of the investigational antiviral remdesivir plus the anti-inflammatory drug baricitinib for coronavirus disease 2019 (COVID-19) has begun.




viral

TV preview: Lucy Worsley's Royal Photo Album; Charlie Brooker's Antiviral Wipe

THE market for TV historians is crowded and fiercely competitive. Drop your guard for a second and Dan Snow or Bettany Hughes will be in the door and taking your gig faster than you can don a pair of those special white gloves all in the trade must have. Lucy Worsley made her name by combining immense knowledge – she is the chief curator at Historic Royal Palaces – with a steadfast dedication to raiding the dressing up box.




viral

Infant Outcomes After Maternal Antiretroviral Exposure in Resource-Limited Settings

Information on infant safety after exposure to maternal antiretroviral regimens during pregnancy in international clinical trials is lacking. As antiretroviral drugs are released to populations in resource-limited settings through clinical trials, it becomes critical to collect pediatric outcome data.

The study demonstrates the feasibility of reporting infant outcomes following adult antiretroviral trials in developing countries, provides HIV-free infant survival and prospective growth data in association with maternal parameters, and details morbidity, mortality, and genetic defects following maternal antiretroviral exposure. (Read the full article)




viral

Mortality and Clinical Outcomes in HIV-Infected Children on Antiretroviral Therapy in Malawi, Lesotho, and Swaziland

There is evidence from both developed and developing countries that antiretroviral treatment significantly reduces mortality in HIV-infected children. However, in sub-Saharan Africa, numerous health system, financial, and human resource obstacles make delivering quality pediatric HIV care a challenge.

We describe the experience of the Baylor International Pediatrics AIDS Initiative in Malawi, Lesotho, and Swaziland. Despite challenges delivering pediatric treatment in these countries, mortality and clinical outcomes approaching those from developed countries are feasible. (Read the full article)




viral

Trends in the Management of Viral Meningitis at United States Children's Hospitals

In the era of widespread conjugate vaccine use, the prevalence of bacterial meningitis has declined. However, the impact of this decline on the rate of emergency department visits for viral meningitis and cost of caring for these children is unknown.

There was a decline in the rate of diagnosis of viral meningitis in US children’s hospitals between 2005 and 2011. Most children diagnosed with viral meningitis are treated with antibiotics and are hospitalized, accounting for considerable health care costs. (Read the full article)




viral

Effectiveness of Nebulized Beclomethasone in Preventing Viral Wheezing: An RCT

Viral wheezing is common in preschool-aged children. The efficacy of inhaled steroids in preventing viral wheezing is debated. Despite this debate, nebulized beclomethasone is widely prescribed (particularly in a few countries) to children with upper respiratory tract infections.

Findings from this study confirm that inhaled steroids are not effective in preventing viral wheezing. Moreover, no differences were found in the persistence of symptoms (eg, runny nose, sore throat) or in the parental perception of asthma-like symptom severity. (Read the full article)




viral

Neuroinvasive Arboviral Disease in the United States: 2003 to 2012

Arthropod-borne viruses are important causes of neurologic infections among children in the United States. The epidemiology of these diseases is complex and relates to multiple factors, including vector biology, animal reservoirs, weather, and human behavior.

National surveillance data from 2003 to 2012 will improve understanding of the geographic, temporal, and clinical trends in pediatric neuroinvasive arboviral disease, and will inform decision-making for clinicians, public health authorities, and the general public. (Read the full article)




viral

Using CD4 Percentage and Age to Optimize Pediatric Antiretroviral Therapy Initiation

In HIV-infected children, decisions to start antiretroviral therapy must weigh immunologic benefits against potential risks. Current guidelines recommend using CD4 percentage and age when deciding to start treatment. Population-level effects of these factors on immunologic recovery are unknown.

Starting antiretroviral therapy at higher CD4 percentages and younger ages maximizes potential for immunologic recovery. However, not all benefits are sustained, and viral failure may occur. Our results help clinicians better weigh immunologic benefits against viral failure risks. (Read the full article)




viral

Diagnosis of Viral Infections Using Myxovirus Resistance Protein A (MxA)

Myxovirus resistance protein A (MxA) is a protein induced during viral infections. A few small-scale studies have suggested that MxA could be used as a marker of viral infection in clinical routine practice.

This study involves the largest patient population thus far and confirms the usefulness of MxA for diagnosing viral infections in children consulting the emergency department in a clinical routine setting. (Read the full article)




viral

Assessment of drug resistance during phase 2b clinical trials of presatovir in adults naturally infected with respiratory syncytial virus [Antiviral Agents]

Background: This study summarizes drug resistance analyses in 4 recent phase 2b trials of the respiratory syncytial virus (RSV) fusion inhibitor presatovir in naturally infected adults.

Methods: Adult hematopoietic cell transplant (HCT) recipients, lung transplant recipients, or hospitalized patients with naturally acquired, laboratory-confirmed RSV infection were enrolled in 4 randomized, double-blind, placebo-controlled studies with study-specific presatovir dosing. Full-length RSV F sequences amplified from nasal swabs obtained at baseline and postbaseline were analyzed by population sequencing. Substitutions at RSV fusion inhibitor resistance-associated positions are reported.

Results: Genotypic analyses were performed on 233 presatovir-treated and 149 placebo-treated subjects. RSV F variant V127A was present in 8 subjects at baseline. Population sequencing detected treatment-emergent substitutions in 10/89 (11.2%) HCT recipients with upper and 6/29 (20.7%) with lower respiratory tract infection, 1/35 (2.9%) lung transplant recipients, and 1/80 (1.3%) hospitalized patients treated with presatovir; placebo-treated subjects had no emergent resistance-associated substitutions. Subjects with substitutions at resistance-associated positions had smaller decreases in viral load during treatment relative to those without, but similar clinical outcomes.

Conclusions: Subject population type and dosing regimen may have influenced RSV resistance development during presatovir treatment. Subjects with vs without genotypic resistance development had decreased virologic responses but comparable clinical outcomes.




viral

MK-571, a cysteinyl leukotriene receptor-1 antagonist, inhibits hepatitis C virus (HCV) replication [Antiviral Agents]

The quinoline MK-571 is the most commonly used inhibitor of multidrug resistance protein-1 (MRP-1) but was originally developed as a cysteinyl leukotriene receptor 1 (CysLTR1) antagonist. While studying the modulatory effect of MRP-1 on anti-hepatitis C virus (HCV) direct acting-antivirals (DAA) efficiency, we observed an unexpected anti-HCV effect of compound MK-571 alone. This anti-HCV activity was characterized in Huh7.5 cells stably harboring a subgenomic genotype 1b replicon. A dose-dependent decrease of HCV RNA levels was observed upon MK-571 administration, with an EC50 of 9±0.3 μM and a maximum HCV RNA level reduction of approximatively 1 Log10. MK-571 also reduced the replication of the HCV full-length J6/JFH1 model in a dose-dependent manner. However, probenecid and apigenin homodimer (APN), two specific inhibitors of MRP-1, had no effect on HCV replication. In contrast, the CysLTR1 antagonists SR2640 increased HCV-SGR RNA levels in a dose-dependent manner, with a maximum increase of 10-fold. In addition, a combination of natural CysLTR1 agonist (LTD4) or antagonists (zafirlukast, cinalukast, and SR2640) with MK-571 completely reversed its antiviral effect, suggesting its anti-HCV activity is related to CysLTR1 rather to MRP-1 inhibition. In conclusion, we showed that MK-571 inhibits HCV replication in hepatoma cell cultures by acting as a CysLTR1 receptor antagonist, thus unraveling a new host-virus interaction in the HCV life cycle.




viral

Rapid-Release Griffithsin Fibers for the Dual Prevention of HSV-2 and HIV-1 Infections [Antiviral Agents]

The biologic Griffithsin (GRFT) has recently emerged as a candidate to safely prevent sexually transmitted infections (STIs) including human immunodeficiency virus (HIV-1) and herpes simplex virus 2 (HSV-2). However, to date, there are few delivery platforms that are available to effectively deliver biologics to the female reproductive tract (FRT). The goal of this work was to evaluate rapid-release polyethylene oxide (PEO), polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP) fibers, that incorporate GRFT, in in vitro (HIV-1 and HSV-2) and in vivo (HSV-2) infection models. GRFT loading was determined via ELISA, and the bioactivity of GRFT fibers was assessed using in vitro HIV-1 pseudovirus and HSV-2 plaque assays. Afterwards, the efficacy of GRFT fibers was assessed in a murine model of lethal HSV-2 infection. Finally, murine reproductive tracts and vaginal lavages were evaluated for histology and cytokine expression, 24 and 72 hr after fiber administration, to determine safety. All rapid-release formulations achieved high levels of GRFT incorporation and were completely efficacious against in vitro HIV-1 and HSV-2 infections. Importantly, all rapid-release GRFT fibers provided potent protection in a murine model of HSV-2 infection. Moreover, histology and cytokine levels, evaluated from collected murine reproductive tissues and vaginal lavages treated with blank fibers, showed no increased cytokine production or histological aberrations, demonstrating the preliminary safety of rapid-release GRFT fibers in vaginal tissue.




viral

Novel ionophores active against La Crosse virus identified through rapid antiviral screening [Antiviral Agents]

Bunyaviruses are significant human pathogens, causing diseases ranging from hemorrhagic fevers to encephalitis. Among these viruses, La Crosse virus (LACV), a member of the California serogroup, circulates in the eastern and midwestern United States. While LACV infection is often asymptomatic, dozens of cases of encephalitis are reported yearly. Unfortunately, no antivirals have been approved to treat LACV infection. Here, we developed a method to rapidly test potential antivirals against LACV infection. From this screen, we identified several potential antiviral molecules, including known antivirals. Additionally, we identified many novel antivirals that exhibited antiviral activity without affecting cellular viability. Valinomycin, a potassium ionophore, was among our top targets. We found that valinomycin exhibited potent anti-LACV activity in multiple cell types in a dose-dependent manner. Valinomycin did not affect particle stability or infectivity, suggesting that it may preclude virus replication by altering cellular potassium ions, a known determinant of LACV entry. We extended these results to other ionophores and found that the antiviral activity of valinomycin extended to other viral families including bunyaviruses (Rift Valley fever virus, Keystone virus), enteroviruses (Coxsackievirus, rhinovirus), flavirivuses (Zika), and coronaviruses (HCoV-229E and MERS-CoV). In all viral infections, we observed significant reductions in virus titer in valinomycin-treated cells. In sum, we demonstrate the importance of potassium ions to virus infection, suggesting a potential therapeutic target to disrupt virus replication.

Importance No antivirals are approved for the treatment of bunyavirus infection. The ability to rapidly screen compounds and identify novel antivirals is one means to accelerate drug discovery for viruses with no approved treatments. We used this approach to screen hundreds of compounds against La Crosse virus, an emerging bunyavirus that causes significant disease, including encephalitis. We identified several known and previously unidentified antivirals. We focused on a potassium ionophore, valinomycin, due to its promising in vitro antiviral activity. We demonstrate that valinomycin, as well as a selection of other ionophores, exhibits activity against La Crosse virus as well as several other distantly related bunyaviruses. We finally observe that valinomycin has activity against a wide array of human viral pathogens, suggesting that disrupting potassium ion homeostasis with valinomycin may be a potent host pathway to target to quell virus infection.




viral

Efficacy of neuraminidase inhibitors against H5N6 highly pathogenic avian influenza virus in a non-human primate model [Antiviral Agents]

Attention has been paid to H5N6 highly pathogenic avian influenza virus (HPAIV) because of its heavy burden on the poultry industry and human mortality. Since an influenza A virus carrying N6 neuraminidase (NA) has never spread in humans, the potential for H5N6 HPAIV to cause disease in humans and the efficacy of antiviral drugs against the virus need to be urgently assessed. We used non-human primates to elucidate the pathogenesis of H5N6 HPAIV as well as to determine the efficacy of antiviral drugs against the virus. H5N6 HPAIV infection led to high fever in cynomolgus macaques. The lung injury caused by the virus was severe with diffuse alveolar damage and neutrophil infiltration. In addition, an increase in IFN-α showed an inverse correlation with virus titers during the infection process. Oseltamivir was effective for reducing H5N6 HPAIV propagation, and continuous treatment with peramivir reduced virus propagation and severity of symptoms in the early stage. This study also showed the pathologically severe lung injury states in the cynomolgus macaques infected with H5N6 HPAIV, even in those that received early antiviral drug treatments, indicating the need for close monitoring and the need for further studies on the virus pathogenicity and new antiviral therapies.




viral

Development of Novel Anti-influenza Thiazolides with Relatively Broad-spectrum Antiviral Potentials [Antiviral Agents]

Seasonal and pandemic influenza causes 650,000 deaths annually in the world. The emergence of drug-resistance to specific anti-influenza drugs such as oseltamivir and baloxavir marboxil highlights the urgency of novel anti-influenza chemical entity discovery. In this study, we report a series of novel thiazolides derived from an FDA-approved drug nitazoxanide with antiviral activity against influenza and a broad range of viruses. The preferred candidates 4a and 4d showed significantly enhanced anti-influenza potentials with 10-fold improvement, compared with nitazoxanide, and were effective against a variety of influenza subtypes including oseltamivir-resistant strains. Notably, the combination using of compounds 4a/4d and oseltamivir carboxylate or zanamivir displayed synergistic antiviral effect against oseltamivir-resistant strain. Mode of action analysis demonstrated that compounds 4a/4d acted at the late phase of viral infection cycle through inhibiting viral RNA transcription and replication. Further experiments showed that treatment with compounds 4a/4d significantly inhibited influenza virus infection in human lung organoids, suggesting the druggability of the novel thiazolides. In-depth transcriptome analysis revealed a series of up-regulated cellular genes that may contribute to the antiviral activities of 4a/4d. Together, our study pointed the optimization direction of nitazoxanide as anti-influenza drug, and discovered two novel-structured candidates 4a/4d with relatively broad-spectrum antiviral potential.




viral

A novel class of chikungunya virus small molecule inhibitors that targets the viral capping machinery [Antiviral Agents]

Despite the worldwide re-emergence of the chikungunya virus (CHIKV) and the high morbidity associated with CHIKV infections, there is no approved vaccine or antiviral treatment available. We here aim to identify the target of a novel class of CHIKV inhibitors i.e. CHVB series. CHVB compounds inhibit the in vitro replication of CHIKV isolates with 50% effective concentrations in the low micromolar range. A CHVB-resistant variant (CHVBres) was selected that carried two mutations in the gene encoding nsP1 (responsible for viral RNA capping), one mutation in nsP2 and one mutation in nsP3. Reverse genetics studies demonstrated that both nsP1 mutations were necessary and sufficient to achieve ~18-fold resistance, suggesting that CHVB targets viral mRNA capping. Interestingly, CHVBres was cross-resistant to the previously described CHIKV capping inhibitors from the MADTP series, suggesting they share a similar mechanism of action. In enzymatic assays, CHVB inhibited the methyltransferase and guanylyltransferase activities of alphavirus nsP1 proteins. To conclude, we identified a class of CHIKV inhibitors that targets the viral capping machinery. The potent anti-CHIKV activity makes this chemical scaffold a potential candidate for CHIKV drug development.




viral

Quercetin blocks Ebola Virus infection by counteracting the VP24 Interferon inhibitory function [Antiviral Agents]

Ebola Virus (EBOV) is among the most devastating pathogens causing fatal hemorrhagic fever in humans. The 2013–2016 epidemics resulted in over 11000 deaths, while another outbreak is currently ongoing. Since there is no FDA-approved drug so far to fight EBOV infection, there is an urgent need to focus on drug discovery. Considering the tight correlation between the high EBOV virulence and its ability to suppress the type-I Interferon (IFN-I) system, identifying molecules targeting viral protein VP24, one of the main virulence determinants blocking IFN response, is a promising novel anti-EBOV therapy approach. Hence, in the effort of finding novel EBOV inhibitors, a screening of a small set of flavonoids was performed, showing that Quercetin and Wogonin can suppress the VP24 effect on IFN-I signaling inhibition. The mechanism of action of the most active compound, Quercetin, showing an IC50 value of 7.4 μM, was characterized to significantly restore the IFN-I signaling cascade, blocked by VP24, by directly interfering with the VP24 binding to karyopherin-α and thus restoring P-STAT1 nuclear transport and IFN genes transcription. Quercetin significantly blocked viral infection, specifically targeting EBOV VP24 anti-IFN-I function. Overall, Quercetin is the first identified inhibitor of the EBOV VP24 anti-IFN function, representing a molecule interacting with a viral binding site that is very promising for further drug development aiming to block EBOV infection at the early steps.




viral

Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs [Antiviral Agents]

Drug repositioning is the only feasible option to address the COVID-19 global challenge immediately. We screened a panel of 48 FDA-approved drugs against SARS-CoV-2 which were pre-selected by an assay of SARS-CoV and identified 24 potential antiviral drug candidates against SARS-CoV-2 infection. Some drug candidates showed very low micromolar IC50s and in particular, two FDA-approved drugs - niclosamide and ciclesonide – were notable in some respects.




viral

Inhibition of SARS-CoV-2 infection by the cyclophilin inhibitor Alisporivir (Debio 025) [Antiviral Agents]

Cyclophilins play a key role in the lifecycle of coronaviruses. Alisporivir (Debio 025) is a non-immunosuppressive analogue of cyclosporin A with potent cyclophilin inhibition properties. Alisporivir reduced SARS-CoV-2 RNA production in a dose-dependent manner in VeroE6 cell line, with an EC50 of 0.46±0.04 μM. Alisporivir inhibited a post-entry step of the SARS-CoV-2 lifecycle. These results justify that a proof-of-concept Phase 2 trial be rapidly conducted with alisporivir in patients with SARS-CoV-2 infection.