447 research outputs found
Monkeypox virus infection in human kidney organoids
No full textHuman kidney organoids were inoculated with monkeypox virus (MPXV), samples at 1 (MPXV1H), 48 (MPXV48H), 96 (MPXV96H) hours and 7 (MPXV7D) days post-inoculation were harvested, and organoids cultured 7 days without infection was included as a negative control. There are 4 replicates for each group. These samples were subjected to genome-wide RNA sequencing. These are the data of RNA-seq on transcriptome
Author response to Letter to the Editor: Hepatitis E prevalence in indigenous communities from Western Brazilian Amazon
No full textRepurposing dyphylline as a pan-coronavirus antiviral therapy
Get PDFBACKGROUND: In the last two decades, the world has witnessed the emergence of zoonotic corona viruses (CoVs), which cause mild to severe respiratory diseases in humans. Human coronaviruses (HCoVs), mainly from the alpha-CoV and beta-CoV genera, have evolved to be highly pathogenic, such as SARS-CoV-2 causing the COVID-19 pandemic. These coronaviruses carry functional enzymes necessary for the virus life cycle, which represent attractive antiviral targets. METHODS & RESULTS: We aimed to therapeutically target the main protease (Mpro) of HCoV-NL63 and HCoV-229E (from alpha-CoV genus) and HCoV-OC43 and SARS-CoV-2 (from beta-CoV genus). Through virtual screening, we identified an FDA-approved drug dyphylline, a xanthine derivate, that binds to the catalytic dyad residues; histidine and cystine of the Mpro structures. Importantly, dyphylline dose-dependently inhibited the viral replication in cell culture models infected with the viruses. CONCLUSION: Our findings support the repurposing of dyphylline as a pan-coronavirus antiviral agent
Differing pan-coronavirus antiviral potency of boceprevir and GC376 in vitro despite discordant molecular docking predictions
No full textGiven the structural similarities of the viral enzymes of different coronaviruses (CoVs), we investigated the potency of the anti-SARS-CoV-2 agents boceprevir and GC376 for counteracting seasonal coronavirus infections. In contrast to previous findings that both boceprevir and GC376 are potent inhibitors of the main protease (Mpro) of SARS-CoV-2, we found that GC376 is much more effective than boceprevir in inhibiting SARS-CoV-2 and three seasonal CoVs (NL63, 229E, and OC43) in cell culture models. However, these results are discordant with a molecular docking analysis that suggested comparable affinity of boceprevir and GC376 for the different Mpro enzymes of the four CoVs. Collectively, our results support future development of GC376 but not boceprevir (although it is an FDA-approved antiviral medication) as a pan-coronavirus antiviral agent. Furthermore, we caution against overinterpretation of in silico data when developing antiviral therapies
Drug Repurposing for Treating Hepatitis E Virus Infection
Get PDFHepatitis E remains a major public health challenge that provokes a tremendous burden of morbidity and mortality worldwide. Since limited treatment options are available, there is a clinical need for further development of new antiviral therapies against HEV infection. Drug repurposing has emerged as an attractive strategy to discover new applications for existing drugs. Thus, there is a clear need for developing drug repurposing of existing medication for treating HEV infection and understanding the potential mechanism-of-action of potent anti-HEV candidates. In this thesis, I propose to systematically screen in a safe-in-human broad-spectrum antiviral agents (BSAAs) library and repurpose the existing drugs that can be readily used in the clinic. I identified several potent inhibits HEV agents and focus on the leading candidates of HEV inhibitors. In Chapter 5, I identified gemcitabine, a widely used anti-cancer drug, potently inhibits HEV infection. Unexpectedly, it functions through the activation of interferon-like response via STAT1 phosphorylation but is independent of Janus kinases. In Chapter 6, I found ivermectin, an FDA-approved anti-parasitic drug, effectively inhibits HEV infection and the mechanism-of-action of ivermectin is associated with the host nuclear transport protein importin α1. In Chapter 7, I showed that macrolide antibiotic azithromycin is a potent HEV inhibitor, and the anti-HEV activity of azithromycin is independent of its induction of interferon-like response. In Chapter 8, I studied niclosamide, a widely used anthelmintic drug, as a potent inhibitor of HEV replication by inhibiting NFκB signaling but independent of STAT3. These findings provide new strategies to develop new antiviral therapies for combating HEV infection
Novel Anti-viral Strategies for Hepatitis C
Get PDFHCV is a single‐stranded positive‐sense RNA virus that was first identified in 19891. HCV belongs to the Flaviviridae family and has six major genotypes. According to the estimation of the World Health Organization, approximately 170 million people, 3% of the world population, are HCV positive with 3 to 4 million de novo infections each year. Of the newly infected individuals only approx. 15‐40% will effectively clear the virus and those who fail to do so will develop a chronic and progressive infection. The prevalence is high in Egypt (>10%), Asia (5‐10%) and Southern Europe (1‐2.5%) and is low in the Netherlands (<1%). Chronic hepatitis C is a slowly progressive disease causing no or few symptoms in the initial phase, but 10 to 20% of the patients develop liver cirrhosis over a period of 10 to 30 years. Patients with liver cirrhosis have an annual risk of 1 to 5% to develop liver cancer, in particular hepatocellular carcinoma (HCC). Unfortunately, there are still no effective vaccines or antibodies available for the prevention of infection
Combating pan-coronavirus infection by indomethacin through simultaneously inhibiting viral replication and inflammatory response
Get PDFSevere infections with coronaviruses are often accompanied with hyperinflammation, requiring therapeutic strategies to simultaneously tackle the virus and inflammation. By screening a safe-in-human broad-spectrum antiviral agents library, we identified that indomethacin can inhibit pan-coronavirus infection in human cell and airway organoids models. Combining indomethacin with oral antiviral drugs authorized for treating COVID-19 results in synergistic anti-coronavirus activity. Coincidentally, screening a library of FDA-approved drugs identified indomethacin as the most potent potentiator of interferon response through increasing STAT1 phosphorylation. Combining indomethacin with interferon-alpha exerted synergistic antiviral effects against multiple coronaviruses. The anti-coronavirus activity of indomethacin is associated with activating interferon response. In a co-culture system of lung epithelial cells with macrophages, indomethacin inhibited both viral replication and inflammatory response. Collectively, indomethacin is a pan-coronavirus inhibitor that can simultaneously inhibit virus-triggered inflammatory response. The therapeutic potential of indomethacin can be further augmented by combining it with oral antiviral drugs or interferon-alpha.</p
No Clear Evidence for an Effect of Sofosbuvir Against Hepatitis E Virus in Organ Transplant Patients
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