scholarly journals M Segment-Based Minigenome System of Severe Fever with Thrombocytopenia Syndrome Virus as a Tool for Antiviral Drug Screening

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1061
Author(s):  
Hiroshi Yamada ◽  
Satoshi Taniguchi ◽  
Masayuki Shimojima ◽  
Long Tan ◽  
Miyuki Kimura ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Rna Synthesis ◽  
Severe Disease ◽  
Treatment Options ◽  
Antiviral Drug ◽  
Case Fatality ◽  
Polymerase Activity ◽  
Small Scale ◽  
Drug Development Research ◽  
Severe Fever

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus that causes severe disease in humans with case fatality rates of approximately 30%. There are few treatment options for SFTSV infection. SFTSV RNA synthesis is conducted using a virus-encoded complex with RNA-dependent RNA polymerase activity that is required for viral propagation. This complex and its activities are, therefore, potential antiviral targets. A library of small molecule compounds was processed using a high-throughput screening (HTS) based on an SFTSV minigenome assay (MGA) in a 96-well microplate format to identify potential lead inhibitors of SFTSV RNA synthesis. The assay confirmed inhibitory activities of previously reported SFTSV inhibitors, favipiravir and ribavirin. A small-scale screening using MGA identified four candidate inhibitors that inhibited SFTSV minigenome activity by more than 80% while exhibiting less than 20% cell cytotoxicity with selectivity index (SI) values of more than 100. These included mycophenolate mofetil, methotrexate, clofarabine, and bleomycin. Overall, these data demonstrate that the SFTSV MGA is useful for anti-SFTSV drug development research.

scholarly journals M Segment-Based Minigenome System of Severe Fever with Thrombocytopenia Syndrome Virus as a Tool for Antiviral Drug Screening

2021 ◽  
Author(s):  
Hiroshi Yamada ◽  
Satoshi Taniguchi ◽  
Masayuki Shimojima ◽  
Long Tan ◽  
Miyuki Kimura ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Rna Synthesis ◽  
Severe Disease ◽  
Treatment Options ◽  
Antiviral Drug ◽  
Case Fatality ◽  
Polymerase Activity ◽  
Small Scale ◽  
Drug Development Research ◽  
Severe Fever

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus that causes severe disease in humans with case fatality rates of approximately 30%. There are few treatment options for SFTSV infection. SFTSV RNA synthesis is conducted using a virus-encoded complex with RNA-dependent RNA polymerase activity that is required for viral propagation. This complex and its activities are, therefore, potential antiviral targets. A library of small molecule compounds was screened using a high-throughput screening (HTS) based on an SFTSV minigenome assay (MGA) in a 96-well microplate format to identify potential lead inhibitors of SFTSV RNA synthesis. The assay confirmed inhibitory activities of previously reported SFTSV inhibitors, favipiravir, and ribavirin. A small-scale screening using MGA identified four candidate inhibitors that inhibited SFTSV minigenome activity by more than 80% while exhibiting less than 20% cell cytotoxicity with selectivity index (SI) values of more than 100. These included mycophenolate mofetil, methotrexate, clofarabine, and bleomycin. Overall, these data demonstrate that the SFTSV MGA is useful for anti-SFTSV drug development research.

scholarly journals Baseline mapping of severe fever with thrombocytopenia syndrome virology, epidemiology and vaccine research and development

npj Vaccines ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Nathen E. Bopp ◽  
Jaclyn A. Kaiser ◽  
Ashley E. Strother ◽  
Alan D. T. Barrett ◽  
David W. C. Beasley ◽  
...  
Keyword(s):  
Severe Disease ◽  
Treatment Options ◽  
Clinical Manifestations ◽  
Case Fatality ◽  
Public Health Problem ◽  
Human Populations ◽  
Hemorrhagic Disease ◽  
Older Individuals ◽  
Tick Vectors ◽  
Severe Fever

AbstractSevere fever with thrombocytopenia syndrome virus (SFTSV) is a newly emergent tick-borne bunyavirus first discovered in 2009 in China. SFTSV is a growing public health problem that may become more prominent owing to multiple competent tick-vectors and the expansion of human populations in areas where the vectors are found. Although tick-vectors of SFTSV are found in a wide geographic area, SFTS cases have only been reported from China, South Korea, Vietnam, and Japan. Patients with SFTS often present with high fever, leukopenia, and thrombocytopenia, and in some cases, symptoms can progress to severe outcomes, including hemorrhagic disease. Reported SFTSV case fatality rates range from ~5 to >30% depending on the region surveyed, with more severe disease reported in older individuals. Currently, treatment options for this viral infection remain mostly supportive as there are no licensed vaccines available and research is in the discovery stage. Animal models for SFTSV appear to recapitulate many facets of human disease, although none of the models mirror all clinical manifestations. There are insufficient data available on basic immunologic responses, the immune correlate(s) of protection, and the determinants of severe disease by SFTSV and related viruses. Many aspects of SFTSV virology and epidemiology are not fully understood, including a detailed understanding of the annual numbers of cases and the vertebrate host of the virus, so additional research on this disease is essential towards the development of vaccines and therapeutics.

scholarly journals Screening of an FDA-Approved Drug Library with a Two-Tier System Identifies an Entry Inhibitor of Severe Fever with Thrombocytopenia Syndrome Virus

Viruses ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 385 ◽  
Author(s):  
Shuofeng Yuan ◽  
Jasper Fuk-Woo Chan ◽  
Zi-Wei Ye ◽  
Lei Wen ◽  
Terance Gi-Wai Tsang ◽  
...  
Keyword(s):  
Severe Disease ◽  
Treatment Options ◽  
Case Fatality ◽  
Test System ◽  
Host Cells ◽  
Entry Inhibitor ◽  
Tier System ◽  
Drug Compounds ◽  
Severe Fever

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus that causes severe disease in humans with case-fatality rates of up to 30%. There are currently very limited treatment options for SFTSV infection. We conducted a drug repurposing program by establishing a two-tier test system to rapidly screen a Food and Drug Administration- (FDA)-approved drug library for drug compounds with anti-SFTSV activity in vitro. We identified five drug compounds that inhibited SFTSV replication at low micromolar concentrations, including hexachlorophene, triclosan, regorafenib, eltrombopag, and broxyquinoline. Among them, hexachlorophene was the most potent with an IC50 of 1.3 ± 0.3 µM and a selectivity index of 18.7. Mechanistic studies suggested that hexachlorophene was a virus entry inhibitor, which impaired SFTSV entry into host cells by interfering with cell membrane fusion. Molecular docking analysis predicted that the binding of hexachlorophene with the hydrophobic pocket between domain I and domain III of the SFTSV Gc glycoprotein was highly stable. The novel antiviral activity and mechanism of hexachlorophene in this study would facilitate the use of hexachlorophene as a lead compound to develop more entry inhibitors with higher anti-SFTSV potency and lower toxicity.

scholarly journals Differences in Viral RNA Synthesis but Not Budding or Entry Contribute to the In Vitro Attenuation of Reston Virus Compared to Ebola Virus

2020 ◽  
Vol 8 (8) ◽  
pp. 1215
Author(s):  
Bianca S. Bodmer ◽  
Josephin Greßler ◽  
Marie L. Schmidt ◽  
Julia Holzerland ◽  
Janine Brandt ◽  
...  
Keyword(s):  
Life Cycle ◽  
Rna Synthesis ◽  
Ebola Virus ◽  
Severe Disease ◽  
Case Fatality ◽  
Viral Rna ◽  
Pathogenic Potential ◽  
Rnp Complex ◽  
Reston Virus

Most filoviruses cause severe disease in humans. For example, Ebola virus (EBOV) is responsible for the two most extensive outbreaks of filovirus disease to date, with case fatality rates of 66% and 40%, respectively. In contrast, Reston virus (RESTV) is apparently apathogenic in humans, and while transmission of RESTV from domestic pigs to people results in seroconversion, no signs of disease have been reported in such cases. The determinants leading to these differences in pathogenicity are not well understood, but such information is needed in order to better evaluate the risks posed by the repeated spillover of RESTV into the human population and to perform risk assessments for newly emerging filoviruses with unknown pathogenic potential. Interestingly, RESTV and EBOV already show marked differences in their growth in vitro, with RESTV growing slower and reaching lower end titers. In order to understand the basis for this in vitro attenuation of RESTV, we used various life cycle modeling systems mimicking different aspects of the virus life cycle. Our results showed that viral RNA synthesis was markedly slower when using the ribonucleoprotein (RNP) components from RESTV, rather than those for EBOV. In contrast, the kinetics of budding and entry were indistinguishable between these two viruses. These data contribute to our understanding of the molecular basis for filovirus pathogenicity by showing that it is primarily differences in the robustness of RNA synthesis by the viral RNP complex that are responsible for the impaired growth of RESTV in tissue culture.

#18: Brincidofovir for the Treatment of Disseminated Human Adenovirus Infection in Pediatric Solid-organ Transplant Recipients

2021 ◽  
Vol 10 (Supplement_1) ◽  
pp. S3-S3
Author(s):  
Jackson Londeree ◽  
Rouba Garro ◽  
Rene Romero ◽  
Roshan George ◽  
Pamela Winterberg ◽  
...  
Keyword(s):  
Antiviral Treatment ◽  
Severe Disease ◽  
Treatment Options ◽  
Graft Loss ◽  
Clinical Specimen ◽  
Antiviral Drug ◽  
Solid Organ Transplantation ◽  
Kidney Injury ◽  
Human Adenovirus ◽  
Solid Organ

Abstract Background Human adenovirus (HAdV) viremia can cause significant morbidity among pediatric patients undergoing solid-organ transplantation (SOT). Currently, there are no US Food and Drug Administration (FDA)-approved treatments for HAdV infections, and historically the mainstay of treatment has been decreasing immunosuppression with antiviral therapies reserved for those with severe disease. Brincidofovir (BCV) is an investigational antiviral drug with potency against HAdV. We describe four cases of disseminated HAdV infection treated with (BCV) among pediatric SOT patients. Methods We retrospectively reviewed 4 cases of severe disseminated HAdV infection, which occurred between 2018 and 2019, in a tertiary pediatric transplant center. HAdV infection was defined as a positive HAdV PCR from a clinical specimen. Baseline clinical characteristics, disease course, treatment, and outcomes were reviewed. Results Four pediatric SOT patients (2 kidneys, 1 dual kidney/liver, and 1 liver) ranging in age from 9 months to 19 years were diagnosed with HAdV infection (Table 1). Patients presented with varied symptoms from 12 to 912 days post-transplant. Peak HAdV viral load ranged from 37,000 to >1,000,000 copies/mL. All patients had disseminated disease with evidence of graft involvement and varying degrees of acute kidney injury (AKI) making them candidates for BCV therapy over cidofovir to avoid nephrotoxicity. Three out of four patients received cidofovir prior to conversion to BCV. IRB-approved compassionate use of BCV was dosed at 2 mg/kg (max 100 mg) twice weekly PO along with reduced immunosuppression. Resolution of symptoms and HAdV viremia was seen at a mean of 21.5 days (range 15–32) of therapy. All patients had resolution of AKI with a return to baseline creatinine after therapy. Conclusions Though HAdV infection in pediatric SOT patients is uncommon, a subset of patients experience severe disease, morbidity, and graft loss. Currently, HAdV is not routinely monitored in pediatric SOT transplant patients. Although supportive care and decreased immunosuppression remain as the most important component of therapy, BCV was well tolerated and efficacious in our series. Further research is needed to better understand risk factors for HAdV infection and potential antiviral treatment options to improve patient outcomes.

scholarly journals High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors

2021 ◽  
Author(s):  
Yao Zhao ◽  
Xiaoyu Du ◽  
Yinkai Duan ◽  
Xiaoyan Pan ◽  
Yifang Sun ◽  
...  
Keyword(s):  
Clinical Trials ◽  
High Throughput Screening ◽  
Treatment Options ◽  
Antiviral Drug ◽  
Binding Pocket ◽  
Binding Mode ◽  
Etiologic Agent ◽  
Drug Candidate ◽  
Approved Drugs ◽  
Pharmacologically Active

AbstractA new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (Mpro), PLpro is responsible for processing the viral replicase polyprotein into functional units. Therefore, it is an attractive target for antiviral drug development. Here we discovered four compounds, YM155, cryptotanshinone, tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 μmol/L. These compounds also exhibit strong antiviral activities in cell-based assays. YM155, an anticancer drug candidate in clinical trials, has the most potent antiviral activity with an EC50 value of 170 nmol/L. In addition, we have determined the crystal structures of this enzyme and its complex with YM155, revealing a unique binding mode. YM155 simultaneously targets three “hot” spots on PLpro, including the substrate-binding pocket, the interferon stimulating gene product 15 (ISG15) binding site and zinc finger motif. Our results demonstrate the efficacy of this screening and repurposing strategy, which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.

scholarly journals A Systematic Review of Treatment Strategies Including Future Novel Therapies in Crimean-Congo Hemorrhagic Fever

2021 ◽  
Vol 8 (2) ◽  
Author(s):  
Hamidreza Kouhpayeh
Keyword(s):  
Systematic Review ◽  
Clinical Efficacy ◽  
Treatment Options ◽  
Antiviral Drug ◽  
Treatment Strategies ◽  
Case Fatality ◽  
Hemorrhagic Fever ◽  
Supportive Treatment ◽  
Crimean Congo Hemorrhagic Fever ◽  
Conclusive Data

Introduction: Crimean-Congo hemorrhagic fever (CCHF) is an acute fetal illness the case fatality rate (CFR), which without treatment is between 26% to more than 80%. Despite the administration of ribavirin as a specific antiviral drug for the treatment of CCHF from many years ago, its clinical efficacy is still controversial. Objectives: This systematic review aimed to evaluate the clinical efficacy of ribavirin, favipiravir, and other treatment options for CCHF, including steroids, immunoglobulin, etc. Method: This systematic review included 31 articles, three factsheet from WHO, CDC, and ECDC, two editorial letters, and two textbooks from 2002 to 2020. The following databases were searched: Google Scholar, PubMed, Medscape, Cochrane, WHO, CDC, and ECDC. Results: The selected results of the above articles were concentrated on the different options of supportive treatment, including steroids, immunoglobulin, etc., as well as the efficacy of antiviral drugs, especially ribavirin and favipiravir. While some studies confirmed the clinical efficacy of ribavirin in the treatment of CCHF, some other studies did not confirm its efficacy. All studies justified that supportive therapies are the mainstay of treatment. Conclusions: The cornerstone of therapy of CCHF is supportive treatment. The clinical efficacy of ribavirin for CCHF treatment is questionable, and further randomized case-control clinical trials are required to confirm and recommend it for CCHF treatment. Also, other treatment strategies, including administration of steroids, immunoglobulin, and monoclonal antibodies (mAbs) require more conclusive data. The promising antiviral drug for CCHF treatment is favipiravir.

scholarly journals In Silico Structure-Based Design of Antiviral Peptides Targeting the Severe Fever with Thrombocytopenia Syndrome Virus Glycoprotein Gn

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2047
Author(s):  
Shuo-Feng Yuan ◽  
Lei Wen ◽  
Kenn Ka-Heng Chik ◽  
Jiang Du ◽  
Zi-Wei Ye ◽  
...  
Keyword(s):  
In Silico ◽  
Cyclic Peptides ◽  
Severe Disease ◽  
Treatment Options ◽  
Clinical Importance ◽  
Host Cells ◽  
Emerging Viruses ◽  
Antiviral Peptides ◽  
Severe Fever

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus in Asia that causes severe disease. Despite its clinical importance, treatment options for SFTSV infection remains limited. The SFTSV glycoprotein Gn plays a major role in mediating virus entry into host cells and is therefore a potential antiviral target. In this study, we employed an in silico structure-based strategy to design novel cyclic antiviral peptides that target the SFTSV glycoprotein Gn. Among the cyclic peptides, HKU-P1 potently neutralizes the SFTSV virion. Combinatorial treatment with HKU-P1 and the broad-spectrum viral RNA-dependent RNA polymerase inhibitor favipiravir exhibited synergistic antiviral effects in vitro. The in silico peptide design platform in this study may facilitate the generation of novel antiviral peptides for other emerging viruses.

scholarly journals Modeling Severe Fever with Thrombocytopenia Syndrome Virus Infection in Golden Syrian Hamsters: Importance of STAT2 in Preventing Disease and Effective Treatment with Favipiravir

2016 ◽  
Vol 91 (3) ◽  
Author(s):  
Brian B. Gowen ◽  
Jonna B. Westover ◽  
Jinxin Miao ◽  
Arnaud J. Van Wettere ◽  
Johanna D. Rigas ◽  
...  
Keyword(s):  
South Korea ◽  
Antiviral Drug ◽  
Case Fatality ◽  
Etiologic Agent ◽  
Genetically Engineered ◽  
Medical Attention ◽  
Type I ◽  
Hamster Model ◽  
Content Type ◽  
Severe Fever

ABSTRACT Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease endemic in parts of Asia. The etiologic agent, SFTS virus (SFTSV; family Bunyaviridae, genus Phlebovirus) has caused significant morbidity and mortality in China, South Korea, and Japan, with key features of disease being intense fever, thrombocytopenia, and leukopenia. Case fatality rates are estimated to be in the 30% range, and no antivirals or vaccines are approved for use for treatment and prevention of SFTS. There is evidence that in human cells, SFTSV sequesters STAT proteins in replication complexes, thereby inhibiting type I interferon signaling. Here, we demonstrate that hamsters devoid of functional STAT2 are highly susceptible to as few as 10 PFU of SFTSV, with animals generally succumbing within 5 to 6 days after subcutaneous challenge. The disease included marked thrombocytopenia and inflammatory disease characteristic of the condition in humans. Infectious virus titers were present in the blood and most tissues 3 days after virus challenge, and severe inflammatory lesions were found in the spleen and liver samples of SFTSV-infected hamsters. We also show that SFTSV infection in STAT2 knockout (KO) hamsters is responsive to favipiravir treatment, which protected all animals from lethal disease and reduced serum and tissue viral loads by 3 to 6 orders of magnitude. Taken together, our results provide additional insights into the pathogenesis of SFTSV infection and support the use of the newly described STAT2 KO hamster model for evaluation of promising antiviral therapies. IMPORTANCE Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral disease for which there are currently no therapeutic options or available vaccines. The causative agent, SFTS virus (SFTSV), is present in China, South Korea, and Japan, and infections requiring medical attention result in death in as many as 30% of the cases. Here, we describe a novel model of SFTS in hamsters genetically engineered to be deficient in a protein that helps protect humans and animals against viral infections. These hamsters were found to be susceptible to SFTSV and share disease features associated with the disease in humans. Importantly, we also show that SFTSV infection in hamsters can be effectively treated with a broad-spectrum antiviral drug approved for use in Japan. Our findings suggest that the new SFTS model will be an excellent resource to better understand SFTSV infection and disease as well as a valuable tool for evaluating promising antiviral drugs.

scholarly journals Screening of a Small Molecule Compound Library Identifies Toosendanin as an Inhibitor Against Bunyavirus and SARS-CoV-2

2021 ◽  
Vol 12 ◽  
Author(s):  
Shufen Li ◽  
Meidi Ye ◽  
Yuanqiao Chen ◽  
Yulan Zhang ◽  
Jiachen Li ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Case Fatality ◽  
Compound Library ◽  
Natural Extracts ◽  
Infection Models ◽  
Mechanistic Investigation ◽  
Small Molecule Compound ◽  
Inhibition Potency ◽  
Severe Fever

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne virus causing serious infectious disease with a high case-fatality of up to 50% in severe cases. Currently, no effective drug has been approved for the treatment of SFTSV infection. Here, we performed a high-throughput screening of a natural extracts library for compounds with activities against SFTSV infection. Three hit compounds, notoginsenoside Ft1, punicalin, and toosendanin were identified for displaying high anti-SFTSV efficacy, in which, toosendanin showed the highest inhibition potency. Mechanistic investigation indicated that toosendanin inhibited SFTSV infection at the step of virus internalization. The anti-viral effect of toosendanin against SFTSV was further verified in mouse infection models, and the treatment with toosendanin significantly reduced viral load and histopathological changes in vivo. The antiviral activity of toosendanin was further expanded to another bunyavirus and the emerging SARS-CoV-2. This study revealed a broad anti-viral effect of toosendanin and indicated its potential to be developed as an anti-viral drug for clinical use.

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