A synthetic stigmastane displays antiadenoviral activity and reduces the inflammatory response to viral infection.
e; LE Abstract Although human adenovirus (ADV) infections are mild and self-limited in immunocompetent individuals, they can be severe and life-threatening in immunocompromised patients. Despite their significant clinical impact, there are not currently approved antiviral therapies for ADV infections. On the other hand, in some cases, the immune response induced by ADV infection can cause tissue damage. Even more, in the case of adenovirus vectors used in gene therapy, host immunity generally antagonize viral efficacy. Therefore, the need for searching an effective and safe therapy is increasing. In this work, we ...
Source: Antiviral Research - September 9, 2020 Category: Virology Authors: Michelini FM, Bueno CA, Areco YB, Alché LE Tags: Antiviral Res Source Type: research

Structural-based virtual screening and in vitro assays for small molecules inhibiting the feline coronavirus 3CL protease as a surrogate platform for coronaviruses.
Abstract Feline infectious peritonitis (FIP) which is caused by feline infectious peritonitis virus (FIPV), a variant of feline coronavirus (FCoV), is a member of family Coronaviridae, together with severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2. So far, neither effective vaccines nor approved antiviral therapeutics are currently available for the treatment of FIPV infection. Both human and animal CoVs shares similar functional proteins, particularly the 3CL protease (3CLpro), which plays the pivotal role on viral replication. We in...
Source: Antiviral Research - September 7, 2020 Category: Virology Authors: Theerawatanasirikul S, Kuo CJ, Phecharat N, Chootip J, Lekcharoensuk C, Lekcharoensuk P Tags: Antiviral Res Source Type: research

A Dengue type 2 reporter virus assay amenable to high-throughput screening.
In conclusion, a powerful and robust assay was developed with a fully automated data generation and processing pipeline. It makes the new reporter virus assay amenable to high-throughput screening of large libraries of small molecules. PMID: 32898584 [PubMed - as supplied by publisher] (Source: Antiviral Research)
Source: Antiviral Research - September 5, 2020 Category: Virology Authors: Li LH, Kaptein SJF, Schmid MA, Zmurko J, Leyssen P, Neyts J, Dallmeier K Tags: Antiviral Res Source Type: research

Identification of a protective epitope in Japanese encephalitis virus NS1 protein.
In this study, we generated five different monoclonal antibodies (mAbs) targeting the NS1 protein of JEV. In vitro experiments revealed that none of these five antibodies neutralized the JEV infection. In mouse protection studies, one of these mAbs, designated 2B8, provided a therapeutic effect against JEV lethal challenge (70% survival rate). Using peptide mapping analysis, we found that mAb 2B8 reacted with the epitope 225PETHTLWGD233 in the NS1 protein, in which any mutations among amino acid residues T228, H229, L231 or W232 could cause binding failure of 2B8 to the NS1 protein. Furthermore, mice immunized with KLH-pol...
Source: Antiviral Research - September 5, 2020 Category: Virology Authors: Zhou D, Pei C, Liu Z, Yang K, Li Q, Chen H, Cao S, Song Y Tags: Antiviral Res Source Type: research

Lassa virus antigen distribution and inflammation in the ear of infected strain 13/N guinea pigs.
Abstract Sudden sensorineuronal hearing loss (SNHL) is reported in approximately one-third of survivors of Lassa fever (LF) and remains the most prominent cause of Lassa virus- (LASV) associated morbidity in convalescence. Using a guinea pig model of LF, and incorporating animals from LASV vaccine trials, we investigated viral antigen distribution and histopathology in the ear of infected animals to elucidate the pathogenesis of hearing loss associated with LASV infection. Antigen was detected only in animals that succumbed to disease and was found within structures of the inner ear that are intimately associated ...
Source: Antiviral Research - September 5, 2020 Category: Virology Authors: Huynh T, Gary JM, Welch SR, Coleman-McCray J, Harmon JR, Kainulainen MH, Bollweg BC, Ritter JM, Shieh WJ, Nichol ST, Zaki SR, Spiropoulou CF, Spengler JR Tags: Antiviral Res Source Type: research

Evaluation of SARS-CoV-2 3C-like protease inhibitors using self-assembled monolayer desorption ionization mass spectrometry.
In conclusion, the SAMDI-MS 3CLpro assay, combined with antiviral and cytotoxic assessment, provides a robust platform to evaluate antiviral agents directed against SARS-CoV-2. PMID: 32896566 [PubMed - as supplied by publisher] (Source: Antiviral Research)
Source: Antiviral Research - September 4, 2020 Category: Virology Authors: Gurard-Levin ZA, Liu C, Jekle A, Jaisinghani R, Ren S, Vandyck K, Jochmans D, Leyssen P, Neyts J, Blatt LM, Beigelman L, Symons JA, Raboisson P, Scholle MD, Deval J Tags: Antiviral Res Source Type: research

Activation of platelet-derived growth factor receptor β in the severe fever with thrombocytopenia syndrome virus infection.
In this study, we screened the protein kinase inhibitors in inhibitory effects on the infection of Vero cells with SFTSV using InhibitorSelect™ Protein Kinase Library Series (Merck & Co., Inc., Kenilworth, NJ, USA). Several types of inhibitors targeted to platelet-derived growth factor receptor β (PDGFRβ) inhibited the infection of Vero, Huh7, and NIH3T3 cells with SFTSV in a dose-dependent manner within the noncytotoxic range. In addition, these protein kinase inhibitors also inhibited the infection of the target cells with SFTSV glycoprotein (SFTSV-GP) pseudotyped virus (SFTSVpv). Activation of PDGFR&...
Source: Antiviral Research - August 31, 2020 Category: Virology Authors: Tani H, Kimura M, Yamada H, Fujii H, Taniguchi S, Shimojima M, Fukushi S, Morikawa S, Saijo M Tags: Antiviral Res Source Type: research

Hepatitis B virus biology and life cycle.
Abstract Hepatitis B virus (HBV) specifically infects hepatocytes and causes severe liver diseases. The HBV life cycle is unique in that the genomic DNA (relaxed-circular partially double-stranded DNA: rcDNA) is converted to a molecular template DNA (covalently closed circular DNA: cccDNA) to amplify a viral RNA intermediate, which is then reverse-transcribed back to viral DNA. The highly stable characteristics of cccDNA result in chronic infection and a poor rate of cure. This complex life cycle of HBV offers a variety of targets to develop antiviral agents. We provide here an update on the current knowledge of H...
Source: Antiviral Research - August 28, 2020 Category: Virology Authors: Tsukuda S, Watashi K Tags: Antiviral Res Source Type: research

ML-SA1, a selective TRPML agonist, inhibits DENV2 and ZIKV by promoting lysosomal acidification and protease activity.
Abstract Arboviruses, especially Dengue virus (DENV) and Zika virus (ZIKV), have been a severe threat to human health in the last few years due to uncontrollable transmission. There are no approved vaccines or clinical drugs available for use to prevent and treat their infections. Transient receptor potential mucolipin 2 and 3 (TRPML2 and TRPML3) were reported to modulate viral entry, but the antiviral function of these modulators was unknown. Here, we reported that ML-SA1, a TRPML agonist, inhibited DENV2 and ZIKV in vitro in a dose-dependent manner. Time-of-drug-addition experiments showed that ML-SA1 mainly res...
Source: Antiviral Research - August 26, 2020 Category: Virology Authors: Xia Z, Wang L, Li S, Tang W, Sun F, Wu Y, Miao L, Cao Z Tags: Antiviral Res Source Type: research

Interference of dengue replication by blocking the access of 3 ´ SL RNA to the viral RNA-dependent RNA polymerase.
Interference of dengue replication by blocking the access of 3´ SL RNA to the viral RNA-dependent RNA polymerase. Antiviral Res. 2020 Aug 21;:104921 Authors: Tunghirun C, Narkthong V, Chaicumpa W, Chimnaronk S Abstract The four circulating serotypes of dengue virus (DENV) occasionally cause potentially fetal symptoms of severe dengue, which there is currently no specific treatment available. Extensive efforts have been made to inhibit viral replication processes by impeding the activity of an exclusive RNA-dependent RNA polymerase (RdRp) in the viral non-structural protein 5 (NS5). In our earlie...
Source: Antiviral Research - August 21, 2020 Category: Virology Authors: Tunghirun C, Narkthong V, Chaicumpa W, Chimnaronk S Tags: Antiviral Res Source Type: research

Vaccine strain of O/ME-SA/Ind-2001e of foot-and-mouth disease virus provides high immunogenicity and broad antigenic coverage.
Abstract Foot-and-mouth disease (FMD) is an economically devastating animal disease. There are seven serotypes, A, O, C, Asia 1, South African Territories 1, 2, and 3 (SAT1, SAT2, and SAT3), among which serotype O shows the greatest distribution worldwide. Specifically, the O/ME-SA/Ind-2001 lineage, which was reported in India in 2001, has since emerged worldwide, with the O/ME-SA/Ind-2001d and O/ME-SA/Ind-2001e sublineages recently emerging in North Africa, Middle East Asia, Southeast Asia, and East Asia. The antigenic relationship (r1) value for the O1 Manisa and O/Mya-98 lineage inactivated vaccine against vari...
Source: Antiviral Research - August 20, 2020 Category: Virology Authors: Lee G, Hwang JH, Park JH, Lee MJ, Kim B, Kim SM Tags: Antiviral Res Source Type: research

Targeting the multifunctional HBV core protein as a potential cure for chronic hepatitis B.
This article forms part of a symposium in Antiviral Research on "Wide-ranging immune and direct-acting antiviral approaches to curing HBV and HDV infections." PMID: 32818519 [PubMed - as supplied by publisher] (Source: Antiviral Research)
Source: Antiviral Research - August 17, 2020 Category: Virology Authors: Viswanathan U, Mani N, Hu Z, Ban H, Du Y, Hu J, Chang J, Guo JT Tags: Antiviral Res Source Type: research

Detection of baloxavir resistant influenza A viruses using next generation sequencing and pyrosequencing methods.
Abstract Baloxavir, a new antiviral drug targeting cap-dependent endonuclease activity of polymerase acidic (PA) protein of influenza viruses, is now approved in multiple countries. Several substitutions at isoleucine 38 in PA protein (e.g., PA-I38T) have been associated with decreased baloxavir susceptibility in vitro and in vivo. In recent years, next generation sequencing (NGS) analysis and pyrosequencing have been used by CDC and U.S. Public Health Laboratories to monitor drug susceptibility of influenza viruses. Here we described an improved pyrosequencing assay for detecting influenza A viruses carrying subs...
Source: Antiviral Research - August 13, 2020 Category: Virology Authors: Patel MC, Mishin VP, De La Cruz JA, Chesnokov A, Nguyen HT, Wilson MM, Barnes J, Kondor RJG, Wentworth DE, Gubareva LV Tags: Antiviral Res Source Type: research

Repurposing Pyramax ®, Quinacrine and Tilorone as Treatments for Ebola Virus Disease.
Repurposing Pyramax®, Quinacrine and Tilorone as Treatments for Ebola Virus Disease. Antiviral Res. 2020 Aug 13;:104908 Authors: Lane TR, Dyall J, Mercer L, Goodin C, Foil DH, Zhou H, Postnikova E, Liang JY, Holbrook MR, Madrid PB, Ekins S Abstract We have recently identified three molecules (tilorone, quinacrine and pyronaridine tetraphosphate) which all demonstrated efficacy in the mouse model of infection with mouse-adapted Ebola virus (EBOV) model of disease and had similar in vitro inhibition of an Ebola pseudovirus (VSV-EBOV-GP), suggesting they interfere with viral entry. Using a machine le...
Source: Antiviral Research - August 13, 2020 Category: Virology Authors: Lane TR, Dyall J, Mercer L, Goodin C, Foil DH, Zhou H, Postnikova E, Liang JY, Holbrook MR, Madrid PB, Ekins S Tags: Antiviral Res Source Type: research

Enzymatically synthesized 2'-fluoro-modified Dicer-substrate siRNA swarms against herpes simplex virus demonstrate enhanced antiviral efficacy and low cytotoxicity.
Abstract Chemical modifications of small interfering (si)RNAs are used to enhance their stability and potency, and to reduce possible off-target effects, including immunogenicity. We have earlier introduced highly effective antiviral siRNA swarms against herpes simplex virus (HSV), targeting 653 bp of the essential UL29 viral gene. Here, we report a method for enzymatic production and antiviral use of 2'-fluoro-modified siRNA swarms. Utilizing the RNA-dependent RNA polymerase from bacteriophage phi6, we produced 2'-F-siRNA swarms containing either all or a fraction of modified adenosine, cytidine or uridine residu...
Source: Antiviral Research - August 13, 2020 Category: Virology Authors: Levanova AA, Kalke KM, Lund LM, Sipari N, Sadeghi M, Nyman MC, Paavilainen H, Hukkanen V, Poranen MM Tags: Antiviral Res Source Type: research

Development of antibody-based assays for high throughput discovery and mechanistic study of antiviral agents against yellow fever virus.
Abstract Despite the availability of a highly effective yellow fever virus (YFV) vaccine, outbreaks of yellow fever frequently occur in Africa and South America with significant mortality, highlighting the pressing need for antiviral drugs to manage future outbreaks. To support the discovery and development of antiviral drugs against YFV, we characterized a panel of rabbit polyclonal antibodies against the three YFV structural proteins and five non-structural proteins and demonstrated these antibody reagents in conjunction with viral RNA metabolic labeling, double-stranded RNA staining and membrane floatation assa...
Source: Antiviral Research - August 13, 2020 Category: Virology Authors: Gao Z, Zhang L, Ma J, Jurado A, Hong SH, Guo JT, Rice CM, MacDonald MR, Chang J Tags: Antiviral Res Source Type: research

Producing Physicochemical Property Consensus Alphavirus Protein Antigens for Broad Spectrum Vaccine Design.
Abstract There is a pressing need for new vaccines against alphaviruses, which can cause fatal encephalitis (Venezuelan equine encephalitis virus (VEEV) and others) and severe arthralgia (e.g. Chikungunya virus, CHIKV). These positive-strand RNA viruses are diverse and evolve rapidly, meaning that the sequence of any vaccine should cover multiple strains that may be quite different from any previous isolate. Here, consensus proteins were produced to represent the common physicochemical properties (PCPs) of the epitope rich, B domain of the E2 envelope protein. PCP-consensus proteins were based on multiple strains ...
Source: Antiviral Research - August 12, 2020 Category: Virology Authors: Baker WS, Negi S, Braun W, Schein CH Tags: Antiviral Res Source Type: research

Viperin protein inhibits the replication of caprine parainfluenza virus 3 (CPIV 3) by interaction with viral N protein.
Abstract Caprine parainfluenza virus type3 (CPIV3) is a newly identified member of Paramyxoviridae family. CPIV3 is highly prevalence in China and showed pathogenecity to goats; in addition, CPIV3 infection causes severe clinical disease under stress and/or co-infection conditions. Viperin is one of the hundreds of interferon-stimulated genes (ISGs), and possesses a wide range of antiviral activities. The aim of this study was to systemically explore the anti-CPIV3 activity of ruminants' Viperin. CPIV3 infection up-regulated Viperin transcription but not protein expression in MDBK cells. Bovine and caprine Viperin...
Source: Antiviral Research - August 12, 2020 Category: Virology Authors: Li W, Li J, Sun M, Yang L, Mao L, Hao F, Liu M, Zhang W Tags: Antiviral Res Source Type: research

Strain-dependent disease and response to favipiravir treatment in mice infected with Chikungunya virus.
Abstract Antiviral countermeasures are needed to reduce the morbidity associated with Chikungunya virus (CHIKV) infection. This arbovirus reemerged in 2004 and causes periodic outbreaks in various areas throughout the world. While infection is rarely lethal, the majority of people infected with the virus develop a hallmark arthralgia as well as other disease manifestations. The virus is classified within three phylogenetic groups, namely, West African, East/Central/South African (ECSA), and Asian. Six strains of CHIKV covering the three phylogenetic groups were studied for their replication in cell culture, their ...
Source: Antiviral Research - August 10, 2020 Category: Virology Authors: Julander JG, Dagley A, Gebre M, Komeno T, Nakajima N, Smee DF, Furuta Y Tags: Antiviral Res Source Type: research

Small molecule inhibitors possibly targeting the rearrangement of Zika virus Envelope protein.
Abstract The recurrent public health threat imposed by Zika Virus (ZIKV) in various geographical areas necessitates the immediate development of antiviral compounds or vaccines. Flaviviral Envelope (E) proteins are essential for host-cell recognition and virion entry. Consequently, they represent an important target for antiviral therapy, with the aim of preventing viral spread during early stages of infection. Due to conformational rearrangement during entry, flavivirus E proteins present several alternative conformations as potential antiviral targets - for blocking entry or virus-host membrane fusion. We previo...
Source: Antiviral Research - August 9, 2020 Category: Virology Authors: Sharma N, Prosser O, Kumar P, Tuplin A, Giri R Tags: Antiviral Res Source Type: research

Iminosugars: a host-targeted approach to combat Flaviviridae infections.
Abstract N-linked glycosylation is the most common form of protein glycosylation and is required for the proper folding, trafficking, and/or receptor binding of some host and viral proteins. As viruses lack their own glycosylation machinery, they are dependent on the host's machinery for these processes. Certain iminosugars are known to interfere with the N-linked glycosylation pathway by targeting and inhibiting α-glucosidases I and II in the endoplasmic reticulum (ER). Perturbing ER α-glucosidase function can prevent these enzymes from removing terminal glucose residues on N-linked glycans, interrupt...
Source: Antiviral Research - August 5, 2020 Category: Virology Authors: DeWald LE, Starr C, Butters T, Treston A, Warfield KL Tags: Antiviral Res Source Type: research

Effect of brincidofovir on adenovirus and A549 cells transcriptome profiles.
CONCLUSION: We demonstrated that BCV alters viral gene expression and promotes the expression of antiviral cellular pathways in A549 cells. These results provide new insights how to interfere with cellular pathways to control HAdV infections. PMID: 32768412 [PubMed - as supplied by publisher] (Source: Antiviral Research)
Source: Antiviral Research - August 5, 2020 Category: Virology Authors: Salmona M, Feghoul L, Mercier-Delarue S, Diaz E, Splitberger M, Armero A, Dalle JH, Dutrieux J, LeGoff J Tags: Antiviral Res Source Type: research

Remdesivir triphosphate can efficiently inhibit the RNA-dependent RNA polymerase from various flaviviruses.
In this study, we tested the ability of remdesivir to inhibit RdRps from the Flaviviridae family. Instead of remdesivir, we used the active species that is produced in cells from remdesivir, the appropriate triphosphate, which could be directly tested in vitro using recombinant flaviviral polymerases. Our results show that remdesivir can efficiently inhibit RdRps from viruses causing severe illnesses such as Yellow fever, West Nile fever, Japanese and Tick-borne encephalitis, Zika and Dengue. Taken together, this study demonstrates that remdesivir or its derivatives have the potential to become a broad-spectrum antiviral a...
Source: Antiviral Research - August 4, 2020 Category: Virology Authors: Konkolova E, Dejmek M, Hřebabecký H, Šála M, Böserle J, Nencka R, Boura E Tags: Antiviral Res Source Type: research

Viral fitness of MHV-68 viruses harboring drug resistance mutations in the protein kinase or thymidine kinase.
Abstract Murine γ-herpesvirus-68 (MHV-68), genetically and biologically related to human γ-herpesviruses Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus, can be easily propagated in vitro allowing drug resistance studies. Previously, we described specific changes in MHV-68 protein kinase (PK) and thymidine kinase (TK) associated with resistance to various purine and pyrimidine nucleoside analogues, respectively. To investigate how specific TK and PK mutations affect viral replication capacity, we performed dual infection competition assays in which wild-type and drug-resistant virus comp...
Source: Antiviral Research - August 4, 2020 Category: Virology Authors: Trompet E, Topalis D, Gillemot S, Snoeck R, Andrei G Tags: Antiviral Res Source Type: research

Crystal structures of full length DENV4 NS2B-NS3 reveal the dynamic interaction between NS2B and NS3.
We report the crystal structures of linked and unlinked NS2B47-NS3 constructs in their free state and in complex with bovine pancreatic trypsin inhibitor (BPTI). These structures demonstrate that the NS2B cofactor predominantly adopts a closed conformation in complex with full-length NS3. The glycine-rich linker between NS2B and NS3 may promote the open conformation which interferes with protease activity. This negative impact on the enzyme structure and function is restricted to the protease activity as the ATPase activity is not affected in vitro. PMID: 32763315 [PubMed - as supplied by publisher] (Source: Antiviral Research)
Source: Antiviral Research - August 4, 2020 Category: Virology Authors: Phoo WW, El Sahili A, Zhang Z, Chen MW, Liew CW, Lescar J, Vasudevan SG, Luo D Tags: Antiviral Res Source Type: research

Animal models for the study of human hepatitis B and D virus infection: new insights and progress.
Abstract Hepatitis B virus (HBV) is a member of the Hepadnaviridae family and infects hepatocytes, leading to liver pathology in acutely and chronically infected individuals. Co-infection with Hepatitis D virus (HDV), which requires the surface proteins of HBV to replicate, can exacerbate this disease progression. Thus, the>250 million people living with chronic HBV infection, including 13 million co-infected with HDV, would significantly benefit from an effective and affordable curative treatment. Animal models are crucial to the development of innovative disease therapies, a paradigm repeated again and again ...
Source: Antiviral Research - August 3, 2020 Category: Virology Authors: Burwitz BJ, Zhou Z, Li W Tags: Antiviral Res Source Type: research

Gamma secretase inhibition impairs HCMV replication by reduction of immediate early gene expression at the transcriptional level.
In this study, we show that treatment with DAPT, a γ-secretase inhibitor (GSI), impairs HCMV replication as assessed by a progeny assay based on immunostaining. This effect is not limited to DAPT because other GSIs with different structures and distinct mechanisms of action also exhibit a similar level of inhibitory effects on HCMV viral production, indicating that γ-secretase activity is required for efficient HCMV replication. Western blot and qPCR analyses reveal that DAPT does not interfere with the viral entry process, but reduces expression of the immediate early protein IE1 at the transcriptional level. ...
Source: Antiviral Research - August 2, 2020 Category: Virology Authors: Lee SM, Han D, Kwon M, Noh H, Ahn JH, Yoon K Tags: Antiviral Res Source Type: research

Comparative pathology study of Venezuelan, eastern, and western equine encephalitis viruses in non-human primates.
This study provides a more complete picture of the pathogenesis of the encephalitic alphaviruses and highlights how further defining the neuropathology of these viruses could have important implications for the development of medical countermeasures for the neurovirulent alphaviruses. PMID: 32755661 [PubMed - as supplied by publisher] (Source: Antiviral Research)
Source: Antiviral Research - August 2, 2020 Category: Virology Authors: Smith DR, Schmaljohn CS, Badger C, Ostrowski K, Zeng X, Grimes SD, Rayner JO Tags: Antiviral Res Source Type: research

Murine norovirus replicase augments RIG-I-like receptors-mediated antiviral interferon response.
This study aims to investigate how murine norovirus (MNV) replicase interacts with RLRs-mediated antiviral IFN response. Counterintuitively, we found that the MNV replicase NS7 enhances the activation of poly (I:C)-induced IFN response and the transcription of downstream interferon-stimulated genes (ISGs). Interestingly, NS7 protein augments RIG-I and MDA5-triggered antiviral IFN response, which conceivably involves direct interactions with the caspase activation and recruitment domains (CARDs) of RIG-I and MDA5. Consistently, RIG-I and MDA5 exert anti-MNV activity in human HEK293T cells with ectopic expression of viral re...
Source: Antiviral Research - August 2, 2020 Category: Virology Authors: Yu P, Li Y, Li Y, Miao Z, Wang Y, Peppelenbosch MP, Pan Q Tags: Antiviral Res Source Type: research

Generation and characterization of Japanese encephalitis virus expressing GFP reporter gene for high throughput drug screening.
In this study, we constructed a full-length infectious clone of eGFP-JEV reporter virus by inserting the eGFP gene into the capsid-coding region of the viral genome. The reporter virus RNA transfected-BHK-21 cells generated robust eGFP fluorescence signals that were correlated well with viral replication. The reporter virus displayed growth kinetics similar to wild type (WT) virus although replicated a little slower. Using a known JEV inhibitor, NITD008, we demonstrated that the reporter virus could be used to identify inhibitors against JEV. Furthermore, an eGFP-JEV-based high throughput screening (HTS) assay was establis...
Source: Antiviral Research - August 1, 2020 Category: Virology Authors: Zhang ZR, Zhang HQ, Li XD, Deng CL, Wang Z, Li JQ, Li N, Zhang QY, Zhang HL, Zhang B, Ye HQ Tags: Antiviral Res Source Type: research

Mutations on VEEV nsP1 relate RNA capping efficiency to ribavirin susceptibility.
Abstract Alphaviruses are arthropod-borne viruses of public health concern. To date no efficient vaccine nor antivirals are available for safe human use. During viral replication the nonstructural protein 1 (nsP1) catalyzes capping of genomic and subgenomic RNAs. The capping reaction is unique to the Alphavirus genus. The whole three-step process follows a particular order: (i) transfer of a methyl group from S-adenosyl methionine (SAM) onto a GTP forming m7GTP; (ii) guanylylation of the enzyme to form a m7GMP-nsP1adduct; (iii) transfer of m7GMP onto 5'-diphosphate RNA to yield capped RNA. Specificities of these r...
Source: Antiviral Research - August 1, 2020 Category: Virology Authors: Nadia R, Oney OG, Gilles Q, Bruno C, Etienne D, Bruno C Tags: Antiviral Res Source Type: research

Functional neuraminidase inhibitor resistance motifs in avian influenza A(H5Nx) viruses.
In this study we introduced four NAI resistance-associated mutations (N2 numbering) previously found in human infections into the NA of three current AIV subtypes of the H5Nx genotype that threaten the poultry industry and human health: highly pathogenic H5N8, H5N6 and H5N2. Using the established MUNANA assay we showed that a R292K substitution in H5N6 and H5N2 viruses significantly reduced susceptibility to three licenced NAIs: oseltamivir, zanamivir and peramivir. In contrast the mutations E119V, H274Y and N294S had more variable effects with NAI susceptibility being drug- and strain-specific. We measured the replicative...
Source: Antiviral Research - August 1, 2020 Category: Virology Authors: Bialy D, Shelton H Tags: Antiviral Res Source Type: research

Substitutions at H134 and in the 430-loop region in influenza B neuraminidases can confer reduced susceptibility to multiple neuraminidase inhibitors.
Abstract With the introduction of the influenza specific neuraminidase inhibitors (NAIs) in 1999, there were concerns about the emergence and spread of resistant viruses in the community setting. Surveillance and testing of community isolates for their susceptibility to the NAIs was initially carried out by the Neuraminidase Inhibitor Susceptibility Network (NISN).and has subsequently been taken on by the global WHO influenza network laboratories. During the NISN surveillance, we identified two Yamagata lineage influenza B viruses with amino acid substitutions of H134Y (B/Auckland/2/2001) or W438R (B/Yokohama/12/2...
Source: Antiviral Research - August 1, 2020 Category: Virology Authors: Mohr PG, Williams J, Tashiro M, Streltsov VA, McKimm-Breschkin JL Tags: Antiviral Res Source Type: research

The chemokine receptor antagonist cenicriviroc inhibits the replication of SARS-CoV-2 in vitro.
In this study, CVC was examined for its inhibitory effect on the replication of SARS-CoV-2, the causative agent of COVID-19, in cell cultures and found to be a selective inhibitor of the virus. The 50% effective concentrations of CVC were 19.0 and 2.9 μM in the assays based on the inhibition of virus-induced cell destruction and viral RNA levels in culture supernatants of the infected cells, respectively. Interestingly, the CCR5-specific antagonist maraviroc did not show any anti-SARS-CoV-2 activity. Although the mechanism of SARS-CoV-2 inhibition by CVC remains to be elucidated, CCR2b does not seem to be its target mol...
Source: Antiviral Research - July 30, 2020 Category: Virology Authors: Okamoto M, Toyama M, Baba M Tags: Antiviral Res Source Type: research

An enzyme-based immunodetection assay to quantify SARS-CoV-2 infection.
ml;nch J, Müller JA Abstract SARS-CoV-2 is a novel pandemic coronavirus that caused a global health and economic crisis. The development of efficient drugs and vaccines against COVID-19 requires detailed knowledge about SARS-CoV-2 biology. Several techniques to detect SARS-CoV-2 infection have been established, mainly based on counting infected cells by staining plaques or foci, or by quantifying the viral genome by PCR. These methods are laborious, time-consuming and expensive and therefore not suitable for a high sample throughput or rapid diagnostics. We here report a novel enzyme-based immunodetection ass...
Source: Antiviral Research - July 29, 2020 Category: Virology Authors: Conzelmann C, Gilg A, Groß R, Schütz D, Preising N, Ständker L, Jahrsdörfer B, Schrezenmeier H, Sparrer KMJ, Stamminger T, Stenger S, Münch J, Müller JA Tags: Antiviral Res Source Type: research

Topoisomerase III- ß is required for efficient replication of positive-sense RNA viruses.
Topoisomerase III-ß is required for efficient replication of positive-sense RNA viruses. Antiviral Res. 2020 Jul 28;:104874 Authors: Prasanth KR, Hirano M, Fagg WS, McAnarney ET, Shan C, Xie X, Hage A, Pietzsch CA, Bukreyev A, Rajsbaum R, Shi PY, Bedford MT, Bradrick SS, Menachery V, Garcia-Blanco MA Abstract Based on genome-scale loss-of-function screens we discovered that Topoisomerase III-ß (TOP3B), a human topoisomerase that acts on DNA and RNA, is required for yellow fever virus and dengue virus-2 replication. Remarkably, we found that TOP3B is required for efficient replication of al...
Source: Antiviral Research - July 28, 2020 Category: Virology Authors: Prasanth KR, Hirano M, Fagg WS, McAnarney ET, Shan C, Xie X, Hage A, Pietzsch CA, Bukreyev A, Rajsbaum R, Shi PY, Bedford MT, Bradrick SS, Menachery V, Garcia-Blanco MA Tags: Antiviral Res Source Type: research

Revisiting HBV resistance to entecavir with a phenotypic approach.
Abstract Treatment adaptation after hepatitis B virus (HBV) treatment failure relies on genotypic resistance testing. However, the results of such tests are not always consistent with treatment response. These discrepancies may be due to differences in resistance levels between isolates with the same genotypic resistance testing profiles. We explored this hypothesis by investigating six cases of entecavir treatment failure with an integrative strategy combining genotypic and phenotypic resistance testing, medical record review and therapeutic drug monitoring. Among isolates with genotypic reduced susceptibility to...
Source: Antiviral Research - July 28, 2020 Category: Virology Authors: Marlet J, Lier C, Roch E, Maugey M, Moreau A, Combe B, Lefeuvre S, d'Alteroche L, Barbereau D, Causse X, Bastides F, Bachelier MN, Brand D, Gaudy-Graffin C Tags: Antiviral Res Source Type: research

A novel method to precisely quantify Hepatitis B Virus covalently closed circular (ccc)DNA formation and maintenance.
Abstract Hepatitis B virus (HBV) is the major cause of viral-associated liver disease. Persistent HBV infection is maintained by its episomal genome (covalently closed circular DNA, cccDNA), which acts as a template for viral transcripts. The formation of cccDNA is poorly characterised due to limited ability to quantify it accurately in the presence of replicative intermediates. Here, we describe a novel cccDNA quantification assay (cccDNA inversion quantitative PCR, cinqPCR), which uses restriction enzymes to invert a DNA sequence close to the gap region of Genotype D HBV strains, including the isolate widely-use...
Source: Antiviral Research - July 26, 2020 Category: Virology Authors: Tu T, Zehnder B, Qu B, Ni Y, Main N, Allweiss L, Dandri M, Shackel N, George J, Urban S Tags: Antiviral Res Source Type: research

Molecular Characterization of Hepatitis C Virus for Subtype Determination and Resistance-Associated Substitutions Detection among Chinese Voluntary Blood Donors.
CONCLUSIONS: Low genetic barriers facilitated the generation of resistance mutants and threated the efficacy of DAA regimens. The baseline RASs posed a great challenge to real-world DAA application. PMID: 32717286 [PubMed - as supplied by publisher] (Source: Antiviral Research)
Source: Antiviral Research - July 24, 2020 Category: Virology Authors: Jiang X, Lv X, Chang L, Yan Y, Ji H, Sun H, Guo F, Rodgers MA, Yin P, Wang L Tags: Antiviral Res Source Type: research

Antiviral activity of Apigenin against buffalopox: Novel mechanistic insights and drug-resistance considerations.
We describe herein that Apigenin, which is a dietary flavonoid, exerts a strong in vitro and in ovo antiviral efficacy against buffalopox virus (BPXV). Apigenin treatment was shown to inhibit synthesis of viral DNA, mRNA and proteins, without affecting other steps of viral life cycle such as attachment, entry and budding. Although the major mode of antiviral action of Apigenin was shown to be mediated via targeting certain cellular factors, a modest inhibitory effect of Apigenin was also observed directly on viral polymerase. We also evaluated the selection of drug-resistant virus variants under long-term selection pressur...
Source: Antiviral Research - July 21, 2020 Category: Virology Authors: Khandelwal N, Chander Y, Kumar R, Riyesh T, Dedar RK, Kumar M, Gulati BR, Sharma S, Tripathi BN, Barua S, Kumar N Tags: Antiviral Res Source Type: research

14-Deoxy-11,12-didehydroandrographolide inhibits apoptosis in influenza A(H5N1) virus-infected human lung epithelial cells via the caspase-9-dependent intrinsic apoptotic pathway which contributes to its antiviral activity.
Abstract Influenza A virus (IAV) infection represents a global health challenge. Excavating antiviral active components from traditional Chinese medicine (TCM) is a promising anti-IAV strategy. Our previous studies have demonstrated that 14-deoxy-11,12-didehydroandrographolide (DAP), a major ingredient of a TCM herb called Andrographis paniculata, shows anti-IAV activity that is mainly effective against A/chicken/Hubei/327/2004 (H5N1), A/duck/Hubei/XN/2007 (H5N1), and A/PR/8/34 (H1N1) in vitro and in vivo. However, the underlying anti-IAV molecular mechanism of DAP needs further investigation. In the present work,...
Source: Antiviral Research - July 20, 2020 Category: Virology Authors: Cai W, Wen H, Zhou Q, Wu L, Chen Y, Zhou H, Jin M Tags: Antiviral Res Source Type: research

Pyronaridine Tetraphosphate Efficacy Against Ebola Virus Infection in Guinea Pig.
Abstract The recent outbreaks of the Ebola virus (EBOV) in Africa have brought global visibility to the shortage of available therapeutic options to treat patients infected with this or closely related viruses. We have recently computationally identified three molecules which have all demonstrated statistically significant efficacy in the mouse model of infection with mouse adapted Ebola virus (ma-EBOV). One of these molecules is the antimalarial pyronaridine tetraphosphate (IC50 range of 0.82-1.30 μM against three strains of EBOV and IC50 range of 1.01-2.72 μM against two strains of Marburg virus (MARV)) wh...
Source: Antiviral Research - July 16, 2020 Category: Virology Authors: Lane TR, Massey C, Comer JE, Freiberg AN, Zhou H, Dyall J, Holbrook MR, Anantpadma M, Davey RA, Madrid PB, Ekins S Tags: Antiviral Res Source Type: research

In vitro evaluation of antiviral activity of single and combined repurposable drugs against SARS-CoV-2.
We report the antiviral effect of remdesivir, lopinavir, chloroquine, umifenovir, berberine and cyclosporine A in Vero E6 cells model of SARS-CoV-2 infection, with estimated 50% inhibitory concentrations of 0.99, 5.2, 1.38, 3.5, 10.6 and 3 μM, respectively. Virus-directed plus host-directed drug combinations were also investigated. We report a strong antagonism between remdesivir and berberine, in contrast with remdesivir/diltiazem, for which we describe high levels of synergy, with mean Loewe synergy scores of 12 and peak values above 50. Combination of host-directed drugs with direct acting antivirals underscore furth...
Source: Antiviral Research - July 14, 2020 Category: Virology Authors: Pizzorno A, Padey B, Dubois J, Julien T, Traversier A, Dulière V, Brun P, Lina B, Rosa-Calatrava M, Terrier O Tags: Antiviral Res Source Type: research

Lower prevalence of antibodies neutralizing SARS-CoV-2 in group O French blood donors.
Abstract We investigated the distribution of antibodies neutralizing SARS-CoV-2 according to age, sex or blood group in French blood donors. In 464 samples collected before the emergence of SARS-CoV-2 (2017 and 2018), our virus neutralization assay had a 100% specificity. It was used to test 998 samples collected from blood donors during the last week of March or the first week of April 2020. As expected at this stage of the outbreak, the prevalence was low (2.7%) and, importantly, criteria for blood donation imply that the vast majority of seropositives had asymptomatic or pauci-symptomatic SARS-CoV-2 infections....
Source: Antiviral Research - July 14, 2020 Category: Virology Authors: Gallian P, Pastorino B, Morel P, Chiaroni J, Ninove L, de Lamballerie X Tags: Antiviral Res Source Type: research

Immunoglobulin fragment F(ab')2 against RBD potently neutralizes SARS-CoV-2 in vitro.
Abstract COVID-19, which is caused by the emerging human coronavirus SARS-CoV-2, has become a global pandemic that poses a serious threat to human health. To date, no vaccines or specific antiviral drugs have been approved for the treatment of this disease in clinic. Herein, therapeutic antibodies for SARS-CoV-2 were obtained from hyperimmune equine plasma. First, a recombinant SARS-CoV-2 spike protein receptor-binding domain (RBD) was obtained in gram-level quantities through high-cell density fermentation of Chinese hamster ovary cells. Then, the binding of the RBD to the SARS-CoV-2 receptor, human angiotensin-c...
Source: Antiviral Research - July 10, 2020 Category: Virology Authors: Pan X, Zhou P, Fan T, Wu Y, Zhang J, Shi X, Shang W, Fang L, Jiang X, Shi J, Sun Y, Zhao S, Gong R, Chen Z, Xiao G Tags: Antiviral Res Source Type: research

Concerns about pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK-PD) studies in the new therapeutic area of COVID-19 infection.
Abstract In the context of the COVID-19 pandemic, several drugs have been repurposed as potential candidates for the treatment of COVID-19 infection. While preliminary choices were essentially based on in vitro potency, clinical translation into effective therapies may be challenging due to unfavorable in vivo pharmacokinetic properties at the doses chosen for this new indication of COVID-19 infection. However, available pharmacokinetic and pharmacokinetic-pharmacodynamic studies suffer from severe limitations leading to unreliable conclusions, especially in term of dosing optimization. In this paper we propose to...
Source: Antiviral Research - July 10, 2020 Category: Virology Authors: Venisse N, Peytavin G, Bouchet S, Gagnieu MC, Garraffo R, Guilhaumou R, Solas C, ANRS-AC43 Clinical Pharmacology Committee, SFPT Therapeutic Drug Monitoring and Treatment Personalization group Tags: Antiviral Res Source Type: research

Characterization of heparin and severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) spike glycoprotein binding interactions.
Abstract Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has resulted in a pandemic and continues to spread around the globe at an unprecedented rate. To date, no effective therapeutic is available to fight its associated disease, COVID-19. Our discovery of a novel insertion of glycosaminoglycan (GAG)-binding motif at S1/S2 proteolytic cleavage site (681-686 (PRRARS)) and two other GAG-binding-like motifs within SARS-CoV-2 spike glycoprotein (SGP) led us to hypothesize that host cell surface GAGs may interact SARS-CoV-2 SGPs to facilitate host cell entry. Using a surface plasmon resonance dire...
Source: Antiviral Research - July 9, 2020 Category: Virology Authors: Kim SY, Jin W, Sood A, Montgomery DW, Grant OC, Fuster MM, Fu L, Dordick JS, Woods RJ, Zhang F, Linhardt RJ Tags: Antiviral Res Source Type: research

Sofosbuvir shows a protective effect against vertical transmission of Zika virus and the associated congenital syndrome in rhesus monkeys.
ra RJ, Soriano A, Bentes GA, de Oliveira Bottino F, Salvador Castro Faria SB, Nudelman RF, Lopes CAA, Perea JAS, Sarges K, Andrade MCR, Motta MCVA, Freire MS, Souza TML, Schmidt-Chanasit J, Pinto MA Abstract The outbreaks of Zika virus (ZIKV) infection in Brazil, 2015-2016, were associated with severe congenital malformations. Our translational study aimed to test the efficacy of the antiviral agent sofosbuvir (SOF) against vertical transmission of ZIKV and the associated congenital syndrome (CZS), using a rhesus monkey model. Eight pregnant macaques were successfully infected during the organogenesis phase with a...
Source: Antiviral Research - July 7, 2020 Category: Virology Authors: Gardinali NR, Marchevsky RS, Oliveira JM, Pelajo-Machado M, Kugelmeier T, Castro MP, Silva ACA, Pinto DP, Fonseca LB, Vilhena LS, Pereira HM, Lima SMB, Miranda EH, Trindade GF, Linhares JHR, Silva SA, Melgaco JG, Alves AMB, Moran J, Silva MCC, Soares-Beze Tags: Antiviral Res Source Type: research

Efficacy of favipiravir (T-705) against Crimean-Congo hemorrhagic fever virus infection in cynomolgus macaques.
In this report we utilized the cynomolgus macaque model to evaluate the efficacy of once- and twice-daily favipiravir treatment against CCHFV infection. We found that favipiravir treatment suppressed viremia and viral shedding when treatment was initiated 24 h post-infection and viral burdens in key tissues trended lower in favipiravir-treated animals. Our data indicate that favipiravir has efficacy against CCHFV in vivo in a non-human primate model of infection. PMID: 32645335 [PubMed - as supplied by publisher] (Source: Antiviral Research)
Source: Antiviral Research - July 6, 2020 Category: Virology Authors: Hawman DW, Haddock E, Meade-White K, Nardone G, Feldmann F, Hanley PW, Lovaglio J, Scott D, Komeno T, Nakajima N, Furuta Y, Gowen BB, Feldmann H Tags: Antiviral Res Source Type: research

A small molecule inhibitor of MyD88 exhibits broad spectrum antiviral activity by up regulation of Type I Interferon.
Abstract Recent studies highlight that infection with Coxsackievirus B3, Venezuelan equine encephalitis virus (VEEV), Marburg virus, or stimulation using poly I:C (dsRNA), upregulates the signaling adaptor protein MyD88 and impairs the host antiviral type I interferon (IFN) responses. In contrast, MyD88 deficiency (MyD88-/-) increases the type I IFN and survivability of mice implying that MyD88 up regulation limits the type I IFN response. Reasoning that MyD88 inhibition in a virus-like manner may increase type I IFN responses, our studies revealed lipopolysaccharide stimulation of U937 cells or poly I:C stimulati...
Source: Antiviral Research - July 1, 2020 Category: Virology Authors: Saikh KU, Morazzani EM, Piper AE, Bakken RR, Glass PJ Tags: Antiviral Res Source Type: research