cord-008716-38sqkh9m	2001	Renewed efforts in vaccine development against respiratory viruses began in the 1960s with the observation that infants and young children, after having recovered from respiratory tract infection with adenoviruses, shed virus from their gastrointestinal tract for an extended period of time without experiencing gastrointestinal symptoms. Earlier studies of viral pathogens in immunocompromised adults indicated that CMV, herpes simplex, influenza, parainfluenza, rhinovirus, adenovirus, enterovirus, and RSV cause lower respiratory infection (Connolly et al., 1994) . Children with RSV, adenovirus or influenza virus infections have a 30% risk of developing AOM within 2 weeks of the onset of the respiratory tract infection (Henderson et al., 1982) , and coinfection with bacteria and viruses also adversely influences the outcome of AOM. Populations at high risk for complications resulting from respiratory viral infections are now better defined and a more targeted prophylaxis is possible, be it passive prophylaxis against RSV disease with monoclonal antibody preparations or active prophylaxis with influenza-or adenovirus vaccines.
cord-008761-b36x05fn	2012	Possessing satisfactory answers to these questions is essential, not only to understand the natural role of the interferon system in virus disease but also to assess possible applications in medicine, in particular the use of interferons or interferoninducing substances as antiviral drugs. Interferon prepared from mouse cell lines infected with Newcastle disease virus is a mixture of a and B (6) . The main difference between these products and their natural-source-derived counterparts is that they contain only a single subtype, namely a2'' While it is known that different subtypes of HuIFN-~ may differ in their antiviral potency depending on the cells on which they are tested, it is not yet known whether this has any repercussion for the clinical effects. Although these side-chains do not playa significant role in the effects of the IFN-S on cells, the pharmacokinetic behavior of this rDd-IFN-S was found to be rather different from that of natural fibroblast-derived interferon (8) .
cord-010247-cug21fnf	1992	A system for evaluating the activity of antiviral agents against Rauscher murine leukemia virus (R-MuLV) has been developed using an enzyme linked immunosorbent assay technique. The assay is based upon detection of R-MuLV encoded p30 protein production in virus infected murine cells. Cytotoxicity evaluations are conducted in parallel to the Rauscher MuLV ELISA assay in order to assess drug-induced reductions in cell viability. Cytotoxicity evaluations are important to interpretation of the ELISA results since reductions in cell viability reduce viral protein production which would indicate an antiviral drug effect. In the case of this compound, the activity detected by the UV-XC plaque reduction assay was believed to result from cytotoxicity to the XC cells used as an overlay. The primary difference between the-ELISA assay and the UV-XC plaque reduction assay is in the drug concentrations required to suppress the virus production endpoint. The UV-XC plaque reduction assay measures the capacity of an antiviral compound to reduce production of infectious virus.
cord-020010-q58x6xb0	2006	In the present study we reported the antiviral activity of neuraminidase inhibitor oseltamivir against lethal H5N1 influenza virus infection in ferrets, an appropriate animal model that closely resembles clinical signs of human influenza. Earl Kern 1 , Kathy Keith 2 , Robert Jordan 2 , Dennis Hruby 2 , Debra Quenelle 2 1 Department of Pediatrics, University of Alabama School of Medicine, Birmingham, AL, USA; 2 SIGA Technologies, Inc., Corvallis, OR, USA Although cidofovir (CDV) has been approved as an investigational new drug for emergency treatment of smallpox, its lack of oral activity and dose limiting toxicity dictates a need for continued development of better therapeutic agents for this potential bioterror disease. The in vitro antiviral activity of one of the most selective compounds, i.e. CHI-033, was assessed by (i) MTS-based cytopathic effect assays, (ii) virus yield reduction assays, (iii) real-time quantitative PCR (RT-QPCR) and (iv) by monitoring viral antigen expression.
cord-023608-w2g7v7g1	2017	ICAR retains its flavor and personality, providing an interdisciplinary forum at which investigators involved in basic, translational, and clinical research worldwide meet to review recent developments in all areas of antiviral research, drug and vaccine development. Additionally, satellite activities such as the Women in Science Roundtable, the Career Development Panel and the New Member and First Time Attendee luncheon (The Happy Hour) provided an opportunity to discuss other issues of relevance. With so many different competing conferences and meetings to attend and a long economic crisis of which scientific research did not escape, ISAR has gone through great financial efforts to continue supporting the participation of students, postdocs and young investigators. The TCFF Awards support the professional development of women with potential to make significant contributions to the field of Antiviral Research by providing funds to attend a conference, visit another laboratory, take a course, or acquire specialized training.
cord-253825-d9borky8	2014	ARB has been shown to display antiviral in vitro and/or in vivo activity against a number of enveloped or non-enveloped RNA or DNA viruses, including influenza viruses A, B and C , respiratory syncytial virus, SARS-CoV, adenovirus, parainfluenza type 5, poliovirus 1, rhinovirus 14, coxsackievirus B5, hantaan virus, Chikungunya virus, HBV and HCV [reviewed in Boriskin et al. Shi and coworkers showed a greater inhibitory effect on influenza A H1N1 when ARB was added before infection or when it was pre-incubated with the virus (Shi et al., 2007) , suggesting that membrane impregnation and/or metabolites could underlie ARB antiviral activity (see Section 6.). Recently, Tannock and coworkers reported a potent antiviral activity of ARB on several virus families responsible of respiratory infections in animals and humans, in particular on influenza A H3N2 (IC50 12 lM), and the non-enveloped Picornaviridae poliovirus 1 and rhinovirus 14 (Brooks et al., 2012 ; see also Brooks et al., 2004) .
cord-254201-hqijd268	2010	Such drugs and antibodies can therefore be thought of as probes for the detection of viral infections, suggesting that they might be used as radiolabeled tracers to visualize sites of viral replication by single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. The only instance in which a pathogen-specific tracer has been employed to detect and track a virus has been the use of a radiolabeled thymidine analogue to image herpes simplex virus (HSV) infections, based on phosphorylation of the probe by the viral thymidine kinase (TK), which traps it within infected cells (Fig. 2) (Brader et al., 2009; Kuruppu et al., 2007) . However, although compounds that inhibit methylation by blocking the host cell enzyme, S-adenosylhomocyteine hydrolase, have potent broad-spectrum antiviral activity, they would not be suitable as virus-specific probes, because they do not bind to a viral target.
cord-255536-x1z2o9gs	2015	The remarkably high guanine content of the Herpes Simplex Virus-1 (HSV-1) genome prompted us to investigate both the presence of G-quadruplex forming sequences in the viral genome and the possibility to target them with G-quadruplex ligands to obtain anti-HSV-1 effects with a novel mechanism of action. BRACO-19 was able to inhibit Taq polymerase processing at G-quadruplex forming sequences in the HSV-1 genome, and decreased intracellular viral DNA in infected cells. In the Epstein-Barr herpes virus (EBV), G-quadruplexes modulate EBV nuclear antigen 1 (EBNA1) activity and translation (Murat et al., 2014) ; in particular, BRACO-19 inhibited EBNA1-dependent stimulation of viral DNA replication http://dx.doi.org/10.1016/j.antiviral.2015.03.016 0166-3542/Ó 2015 Elsevier B.V. All rights reserved. We demonstrate that treatment with the G-quadruplex ligand BRACO-19 greatly stabilizes these sequences resulting in decrease of infectious viral particles, reduction of late viral transcripts, inhibition of Taq polymerase processing at the HSV-1 genome, specifically affecting viral DNA replication at G-quadruplex regions.
cord-255902-fxlbx84w	2015	In this study, we investigated whether these lozenges also have virucidal effects in vitro against two viruses associated with respiratory tract infections, parainfluenza virus type 3 and cytomegalovirus. These findings suggest that AMC/DCBA lozenge and hexylresorcinol lozenge have the potential to have local antiviral effects in patients with sore throat due to viral respiratory tract infections. AMC/DCBA lozenges have also been shown to have some virucidal effects in vitro on three enveloped viruses -RSV, influenza A virus and severe acute respiratory syndrome coronavirus (SARS-CoV) (Oxford et al., 2005) . This study investigated the in vitro virucidal activity of AMC/ DCBA alone and in a lozenge on two other enveloped viruses that can cause sore throat and respiratory illness -PIV type 3 (PIV3) and CMV (Bisno, 2001) . Taken together, these data support the use of these lozenges as a first-line treatment for sore throat caused by viral RTIs. Further investigation into the mechanisms of action and the clinical effects of AMC/DCBA and hexylresorcinol for the control of RTIs is warranted.
cord-256270-7e8zlt3t	2020	We evaluated the in vitro antiviral effect of compounds that were previously reported to inhibit coronavirus replication and compounds that are currently under evaluation in clinical trials for SARS-CoV-2 patients. We report the antiviral effect of remdesivir, lopinavir, homorringtonine, and emetine against SARS-CoV-2 virus in Vero E6 cells with the estimated 50% effective concentration at 23.15 μM, 26.63 μM, 2.55 μM and 0.46 μM, respectively. Among the 16 compounds we tested, remdesivir, lopinavir, homoharringtonine, and emetine dihydrochloride were found to inhibit SARS-CoV-2 replication in Vero E6 cells with EC 50 under 100 μM (Table 1) . Importantly, we observed that some of the compounds currently undergoing clinical trials such as ribavirin, favipiravir, oseltamivir, or baloxavir showed no apparent antiviral effect against the SARS-CoV-2 virus in vitro at concentrations under 100 μM (Table 1) .
cord-256280-ihj102hi	2017	title: The cholesterol transport inhibitor U18666A inhibits type I feline coronavirus infection In this study, we investigated whether U18666A, the cholesterol synthesis and transport inhibitor, shows antiviral effects against type I FCoV. U18666A induced cholesterol accumulation in cells and inhibited type I FCoV replication. These findings suggest that cell membrane cholesterol plays an important role in type I FCoV infection. In order to confirm the effects of the accumulation of cholesterol on FCoV infection, fcwf-4 cells were pretreated with U18666A, followed by virus inoculation. When cells were pretreated with cholesterol biosynthesis inhibitors, only itraconazole significantly inhibited FCoV-I KU2 plaque formation. In addition, treatment of cells with U18666A did not influence the cellular cholesterol level, suggesting that U18666A inhibits type I FCoV replication at a concentration suppressing cholesterol transporter but not influencing the synthesis system. It was suggested that U18666A inhibits type I FCoV replication by suppressing the intracellular cholesterol transporter.
cord-257271-jzmwy4yi	2008	Previously we showed that GL inhibits Epstein-Barr virus (EBV) infection in vitro by interfering with an early step of the EBV replication cycle (possibly attachment/penetration). In previous years, we have shown that many nucleoside analogs selectively inhibit replication of Epstein-Barr virus (EBV) in vitro (Lin et al., 1983 (Lin et al., , 1984 (Lin et al., , 1985 (Lin et al., , 1987 (Lin et al., , 1991 (Lin et al., , 1992 Lin and Machida, 1988; Mar et al., 1995; for a review see Gershburg and Pagano, 2005; Lin, 2006) . As an assay system for drug effects we used Raji cells superinfected with P3HR-1 (LS) virus, which results in reactivation of the latent EBV infection and replication of virus. To determine the dose-dependent effect of GL derivatives, Raji cells were superinfected with P3HR-1 (LS) virus in the presence of various concentrations of compounds.
cord-259480-1tqfoecc	2016	To design an alternative vaccine for control of infectious bronchitis in chickens, three recombinant duck enteritis viruses (rDEVs) expressing the N, S, or S1 protein of infectious bronchitis virus (IBV) were constructed using conventional homologous recombination methods, and were designated as rDEV-N, rDEV-S, and rDEV-S1, respectively. After challenge with a homologous virulent IBV strain at 21 days post-immunization, vaccinated groups showed significant differences in the percentage of birds with clinical signs, as compared to the control group (p < 0.01), as the two covalent-vaccination groups and the rDEV-S group provided better protection than the rDEV-Nor rDEV-S1-vaccinated group. The N phosphoprotein is conserved among different IBV serotypes and can induce high titers of cross-reactive antibodies and cell-mediated immunity that protects chickens from acute infection, thus it is used as a target protein in designing vaccines against IB (Williams et al., 1992; Collisson et al., 2000; Seo et al., 1997) . Antibody responses of chickens vaccinated with recombinant duck enteritis viruses expressing the N, S or S1 gene of infectious bronchitis virus (IBV).
cord-260071-z29b30sd	2005	All of these compounds are assumed to exert their anti-HIV activity by shielding the positively charged sites in the V3 loop region of the viral gp120 envelope glycoprotein, and interrupting virus attachment to the negatively charged heparan sulfate proteoglycans on cell surface, and inhibiting the specific binding to the CD4 receptor of CD4 + cells. PHA (1 g/ml, Sigma-Aldrich)/IL-2 (100 U/ml, Shionogi, Osaka, Japan) activated PBMCs were infected for 2 h with 20 ng of HIV-1 p24 Gag (X4/NL4-3 or R5/JRCSF) in the presence or absence of the Sukumo extract (0.64-400 g/ml), washed three times with PBS and cultured for 7 days in RPMI-1640 medium/10% FBS plus 100 U/ml IL-2 with or without the Sukumo extract. Sukumo extract was also evaluated for the inhibition of wild-type herpes simplex virus-1 replication in infected Vero cells, using a standard viral plaque assay (Fig. 1B) .
cord-260735-3c33r1os	2008	In this paper, we report an original finding that two redox-modulating agents, the ethacrynic and α-lipoic acids (EA, LA), inhibit growth of vaccinia virus (VACV) in vitro. Therefore, we have first compared the effect of different redox-modulating agents on the growth of VACV, characterized by activity of luciferase expressed by a rVACV. HeLa G cells were infected with a rVACV expressing luciferase under control of a VACV late promoter p4b (Luc L; The results indicated that all tested concentrations of ␤mercapthoethanol, dithiothreitol and l-ascorbic acid significantly increased luciferase activity expressed by rVACV (500 M concentration of these agents increased luciferase activity to 150, 140, and 120% of the mock-treated controls; p < 0.05). In contrast to EA and LA, none of these agents inhibited VACV growth in HeLa G cells characterized by activity of the reporter luciferase expressed by a rVACV.
cord-262110-569a86u3	2014	Octaguanidinium-conjugated morpholino oligomers (vivo-MOs) are single-stranded DNA-like antisense agents that can readily penetrate cells and reduce gene expression by steric blocking of complementary RNA sequences. In this study, three octaguanidinium dendrimer conjugatedmorpholino oligomers (vivo-MOs) targeting the EV-71 internal ribosome entry site (IRES) core sequence and the RNA-dependent RNA polymerase (RdRP) were tested for their inhibitory effects against EV-71. After incubation, the inoculum was removed and replenished with maintenance medium (DMEM with 2% FBS) with or without vivo-MOs. The inhibitory effects of the vivo-MOs were evaluated by plaque assay, TaqMan real-time RT-PCR and western blot analysis 24 h post-infection (hpi) as previously described (Tan et al., 2012 . As shown in Fig. 2 , both vivo-MOs targeting the EV-71 IRES stemloop region exhibited significant antiviral activity against EV-71 infection with reduction of virus-induced CPE ( Fig. 2A) , plaque formation (Fig. 2B) , RNA (Fig. 2C ) and capsid expression (Fig. 2D ) in a dose-dependent manner.
cord-262184-uxyb4vih	2020	We previously demonstrated that five nucleotide analogues inhibit the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), including the active triphosphate forms of Sofosbuvir, Alovudine, Zidovudine, Tenofovir alafenamide and Emtricitabine. Using the criteria above, our study examines 11 nucleotide analogues with sugar or base modifications (structures shown in Fig. 1 ) for their ability to inhibit the SARS-CoV-2 or SARS-CoV RdRps: Ganciclovir 5''-triphosphate, Carbovir 5''-triphosphate, Cidofovir diphosphate, Stavudine 5''-triphosphate, Entecavir 5''-triphosphate, 2''-O-methyluridine-5''-triphosphate (2''-OMe-UTP), 3''-O-methyluridine-5''triphosphate (3''-OMe-UTP), 2''-fluoro-2''-deoxyuridine-5''-triphosphate (2''-F-dUTP), desthiobiotin-16aminoallyl-uridine-5''-triphosphate (Desthiobiotin-16-UTP), biotin-16-aminoallyl-2''-deoxyuridine-5''triphosphate (Biotin-16-dUTP) and 2''-amino-2''-deoxyuridine-5''-triphosphate (2''-NH 2 -dUTP). We then performed polymerase extension assays with the library of nucleoside triphosphate analogues (Fig. 1) either alone or in combination with natural nucleotides: 2''-OMe-UTP, 3''-OMe-UTP, 2''-F-dUTP, 2''-NH 2 -dUTP, Biotin-UTP, desthiobiotin-16-UTP, Sta-TP, Cid-DP + UTP + ATP, Car-TP + UTP + ATP + CTP, Gan-TP + UTP + ATP + CTP, or Ent-TP + UTP + ATP + CTP, following the addition of a pre-annealed RNA template and primer to a pre-assembled mixture of the SARS-CoV and/or SARS-CoV-2 RdRp (nsp12) and the two cofactor proteins (nsp7 and nsp8).
cord-263042-qdmunb9l	2016	Passive transfer of equine immune antibodies significantly reduced virus titers and accelerated virus clearance from the lungs of MERS-CoV infected mice. Our data show that horses immunized with MERS-CoV VLPs can serve as a primary source of protective F(ab'')(2) for potential use in the prophylactic or therapeutic treatment of exposed or infected patients. Several research groups have developed and produced anti-MERS patientderived or humanized monoclonal neutralizing antibodies in vitro that were able to protect MERS-CoV infected mice (Corti et al., 2015; Li et al., 2015; Zhao et al., 2014) . Prophylactic or therapeutic treatment of MERS-CoV infected mice with either IgG or F(ab'') 2 significantly decreased the virus load in their lungs. In both prophylactic and therapeutic settings, passive transfer of equine immune antibodies resulted in a 2e4 log reduction of virus titers in the lungs of MERS-CoV infected mice, and accelerated virus clearance in the serum treated group (Fig. 5A, B) .
cord-264308-y6xuxj16	2015	In this study, we established an ex vivo model using mouse lung slices to evaluate both antiviral and anti-inflammatory agents against influenza virus infection. Our results suggested that mouse lung slices provide a robust, convenient and cost-efficient model for the assessment of both antiviral and anti-inflammatory agents against influenza virus infection in one assay. Our results showed that the lung slice model provides a robust, convenient and cost-economical method for the screening and evaluation of both antiviral and anti-inflammatory agents against influenza virus infection in one assay. To meet the goal of this study in the establishment of an ex vivo mouse slice model for the screening and evaluation of both antiviral and anti-inflammatory drugs against influenza infection in one assay, ensuring that the ex vivo model has similar patterns in influenza-induced cytokine and chemokine responses is critical.
cord-264488-989t9ld1	2014	In the present study, the potential antiviral activity of RNase L against hepatitis B virus (HBV) was explored utilizing the recently reported infection protocol based on human hepatoma HepG2 cells stably complemented with the virus entry factor NTCP. These results suggest that HBV replication can be regulated through interferon-mediated RNA decay pathways and that activation of these host antiviral factors may represent a novel therapeutic strategy for HBV infection. Our data indicate that ligand-mediated activation of these enzymes results in a marked inhibition of HBV replication in both infected and transfected cells. With the newly established HepG2-NTCP cell culture system, which permits HBV infection, we showed that viral gene expression and replication can be profoundly reduced by 2-5Aor poly(I:C)-mediated activation of RNase L. In HBV1.2-transfected Huh-7 cells, it was further confirmed that this type of inhibition occurred mostly through viral RNA degradation via the ribonuclease function of RNase L.
cord-266520-n439dwcx	2020	The antiviral efficacy of the 2''-F-siRNA swarms and the elicited cellular innate responses did not correlate suggesting that innate immunity pathways do not significantly contribute to the observed enhanced antiviral activity of the modified siRNAs. The results support further applications of enzymatically produced siRNA molecules with incorporated adenosine nucleotides, carrying fluoro-modification on ribose C2'' position, for further antiviral studies in vitro and in vivo. We have previously generated three antiviral siRNA swarms against herpes simplex virus type 1 (HSV-1) mRNAs encoding essential viral proteins, including glycoprotein B (UL27), the infected cell protein 8 (ICP8; UL29), and ICP27 (UL54) (Romanovskaya et al., 2012; Paavilainen et al., 2016) . The siRNA swarm targeting mRNA of HSV single-stranded DNA binding protein ICP8, encoded by the UL29 gene, harbors a most pronounced antiviral effect (Paavilainen et al., 2016) and induces only minimal non-specific cellular responses (Romanovskaya et al., 2012) .
cord-270364-lsfmcj5c	2010	Comparing these results with some obtained previously with chlorhexidine and hexamidine, (i) these two calixarenes did not show any cytotoxicity contrary to chlorhexidine and hexamidine, (ii) C[4]S showed as did hexamidine, a very weak activity against HCoV 229E, and (iii) the C[4]S-BTZ showed a stronger activity than chlorhexidine, i.e. 2.7 and 1.4 log 10 reduction in viral titer after 5 min of contact with 10 −3 mol L −1 solutions of C[4]S-BTZ and chlorhexidine, respectively. Comparing these results with some obtained previously with chlorhexidine and hexamidine, (i) these two calixarenes did not show any cytotoxicity contrary to chlorhexidine and hexamidine, (ii) C[4]S showed as did hexamidine, a very weak activity against HCoV 229E, and (iii) the C[4]S-BTZ showed a stronger activity than chlorhexidine, i.e. 2.7 and 1.4 log 10 reduction in viral titer after 5 min of contact with 10 −3 mol L −1 solutions of C[4]S-BTZ and chlorhexidine, respectively.
cord-270498-hh6h50t2	2017	Celastrol-induced heme oxygenase 1 (HO-1) expression promoted antiviral interferon responses and inhibition of NS3/4A protease activity, thereby blocking HCV replication. These antiviral effects were abrogated by treatment with the HO-1-specific inhibitor SnMP or silencing of HO-1 expression by transfection of shRNA, which indicates that HO-1 induction contributes to the anti-HCV activity of celastrol. In this study, our data revealed that celastrol significantly inhibits HCV replication, and that the anti-HCV effect of celastrol was attenuated by the HO-1 specific inhibitor tin mesoporphyrin (SnMP) or HO-1 gene expression silencing. Celastrol-mediated HO-1 induction contributed to the anti-HCV action through inducing antiviral IFN response and inhibiting HCV NS3 protease activity. As shown in Fig. 7B , HO-1 RNA expression levels were induced by celastrol compared with non-celastrol treated cells and the JNK inhibitor SP600125 significantly reduced the HO-1 inductive effect of celastrol. In the present study, we found that a natural product celastrol could effectively inhibit HCV NS3/4A protease activity and enhance IFN-mediated antiviral gene expression through HO-1 induction (Figs.
cord-271638-0wsyl7vk	2020	Therefore, the natural dietary flavonoid myricetin has potential to be developed into a novel anti-HSV agent targeting both virus gD protein and cellular EGFR/PI3K/Akt pathway. As shown in Fig. 2C and E, myricetin treatment (20 μM) during adsorption significantly decreased the fluorescence of ICP5 protein on cell surface, compared to that in non-treated virus control cells, suggesting that myricetin may block virus adsorption process of HSV. As shown in Fig. 3A , in HSV-2 (MOI = 3.0) infected Vero cells, obvious syncytia with multinuclear cells were observed in non-treated virus control group (HSV-2) at 7 h p.i. However, treatment with myricetin (30, 15 μM) during 5-7 h p.i. markedly blocked syncytium formation only with a limited number of small syncytia, suggesting that myricetin may inhibit HSV-induced cell fusion. However, myricetin (2.5, 5, 10, 20 μM) treatment did not significantly influence the total expression levels of EGFR, PI3K and Akt proteins in HSV-2 infected Vero cells (Fig. 4G and H) .
cord-275624-o5545c1x	2020	Here, we constructed a series of SARS-CoV RBD mutant proteins based on the 176 interaction between the RBD and viral receptor (Li et al., 2005) , and performed an 177 ELISA to test binding ability of the above mAbs to these mutant proteins. In addition, control mAb 33G4 only blocked SARS-CoV 201 RBD, but not SARS-CoV-2 RBD, binding to the ACE2 receptor (Fig. 4B, C) , partially 202 explaining why this mAb did not neutralize SARS-CoV-2 infection. 203 Moreover, the two cross-neutralizing mAbs, 18F3 and 7B11, respectively recognized 227 two conserved, as well as several non-conserved, neutralizing epitopes on the RBDs of 228 SARS-CoV and SARS-CoV-2. 318 Characterization of the receptor-binding domain (RBD) of 2019 novel 319 coronavirus: implication for development of RBD protein as a viral attachment 320 inhibitor and vaccine (B) Inhibition of SARS-CoV RBD-specific mAbs for 411 the binding of SARS-CoV or SARS-CoV-2 RBD to ACE2 receptor by flow 412 cytometry analysis.
cord-277443-mv7sk5aa	2016	Hiltonol(®) at 5, 1, 0.5 or 0.25 mg/kg/day by intranasal (i.n.) route resulted in significant survival benefit when administered at selected times 24 h prior to challenge with a lethal dose of mouse-adapted severe acute respiratory syndrome coronavirus (SARS-CoV). In other studies, treatment with an interferon inducer, polyriboinosinicpolyribocytidylic acid stabilized with poly-L-lysine and carboxymethyl cellulose (poly IC:LC), given by the intranasal route, was effective in protecting mice against a lethal infection with mouseadapted SARS-CoV and reduced viral lung titers (Kumaki et al., 2010) . These treated, SARS-CoVinfected mice receiving the various Hiltonol ® dosing regimens were also significantly protected against weight loss due to virus infection (Table 1 , p < 0.05-p<0.001) from days 0e3 post virus exposure when the greatest weight loss occurred in this mouse model.
cord-277860-vzyrcmu4	2020	In vitro evaluation of antiviral activity of single and combined repurposable drugs 1 against SARS-CoV-2 2 3 Authors: Andrés Pizzorno a , Blandine Padey a,b , Julia Dubois a , Thomas Julien a,c , Aurélien 4 Traversier a , Victoria Dulière a,c , Pauline Brun a,c , Bruno Lina a,d , Manuel Rosa-Calatrava a,c* † , 5 Olivier Terrier a* † 6 7 Author affiliations: Abstract: 27 In response to the current pandemic caused by the novel SARS-CoV-2, identifying and 28 validating effective therapeutic strategies is more than ever necessary. We evaluated the in 29 vitro antiviral activities of a shortlist of compounds, known for their cellular broad-spectrum 30 activities, together with drugs that are currently under evaluation in clinical trials for COVID-31 19 patients. We evaluated the in 29 vitro antiviral activities of a shortlist of compounds, known for their cellular broad-spectrum 30 activities, together with drugs that are currently under evaluation in clinical trials for COVID-31 19 patients.
cord-278876-il7g78w1	2017	This report highlights the accomplishments of GVN researchers in many priority areas of medical virology, including the current Zika epidemic, infections by human papillomavirus, influenza, Ebola, Lassa, dengue, HIV, hepatitis C, and chikungunya viruses, and the development of improved diagnostics and new vaccines. This meeting report highlights accomplishments of GVN researchers in many priority areas of human virology, including the current Zika epidemic, infections by human papillomavirus, influenza, Ebola, Lassa, dengue, HIV, hepatitis C and chikungunya viruses, and the development of improved diagnostics and new vaccines. The main objectives of the meeting were to present and discuss current findings in medical virology, including advances in research on HIV vaccines and other important retroviruses; provide a framework to encourage collaborations among world experts; and address the GVN''s annual strategy for continued development. Hideki Hasegawa, a GVN center director at the National Institute of Infectious Diseases in Tokyo, explained that secretory IgA antibodies on mucosal surfaces play an important role in protection against influenza virus infection.
cord-281069-m638nyt0	2013	Both Hp1036 and Hp1239 peptides exhibited potent virucidal activities against HSV-1 (EC(50) = 0.43 ± 0.09 and 0.41 ± 0.06 μM, respectively) and effective inhibitory effects when added at the viral attachment (EC(50) = 2.87 ± 0.16 and 5.73 ± 0.61 μM, respectively), entry (EC(50) = 4.29 ± 0.35 and 4.32 ± 0.47 μM, respectively) and postentry (EC(50) = 7.86 ± 0.80 and 8.41 ± 0.73 μM, respectively) steps. An extended peptide from bovine, indolicidin, showed a direct inactivation effect on cell-free HSV-1 virons by targeting viral membrane/ glycoprotein (Albiol Matanic and Castilla, 2004 Natural AMPs from scorpion venoms have attracted much attention due to their anti-viral bioactivities. To determine whether Hp1036 and Hp1239 could inhibit HSV-1 infection or replication in Vero cells, 10 lM of each peptide was added to the virus or cells at different times relative to incubation (Fig. 3A) . Various concentrations of peptides were added to Vero cells 1 h before HSV-1 infection and the inhibitory effects were determined by plaque assay.
cord-281385-oxohdfpu	2014	Crystal structures of almost all available flavivirus methyltransferases contain S-adenosyl-L-methionine (SAM), the methyl donor molecule that co-purifies with the enzymes. The SAM-depleted and SAM-containing MTases exhibited comparable enzymatic activities (N-7 MTase, 2 0 -O MTase, and covalent GMP-MTase complex formation the natural product Sinefungin, showing that this is a viable approach to identify novel small molecules that bind to the same pocket. This conclusion was supported by two complementary structural and functional approaches: (i) the crystal structure unequivocally shows that absence of SAM does not affect the overall conformation of DENV MTase, including the SAM-binding pocket; (ii) depletion of SAM from the recombinant MTase did not change the activities of cap methylations and GMP-MTase complex formation. Structural and functional analysis of methylation and 5 0 -RNA sequence requirements of short capped RNAs by the methyltransferase domain of dengue virus NS5
cord-283739-p7b4mtbl	2020	We investigated the potential drug-liked compounds and their inhibitory interaction on the 3CL(pro) active sites of CoVs by the structural-bases virtual screening. Evaluation of antiviral activity using cell-based assay showed that NSC629301 and NSC71097 could strongly inhibit the cytopathic effect and also reduced replication of FIPV in CRFK cells in all examined conditions with the low range of EC(50) (6.11 ± 1.90 to 7.75 ± 0.48 μM and 1.99 ± 0.30 to 4.03 ± 0.60 μM, respectively), less than those of ribavirin and lopinavir. According to the FIPV 3CL pro structurral based study, we determined if the candidate 293 compounds that could bind to the active site and inhibited the protease activity still actively 294 Cys144 and His41, the active residues of FIPV 3CL pro , formed the π-alkyl interaction 352 and hydrogen bond to the compounds, respectively.
cord-284076-087oltss	2007	Of 12 peptide-conjugated PMO (PPMO), four were found to be highly effective at inhibiting PRRSV replication in cell culture in a dose-dependant and sequence-specific manner. In a previous study (Zhang et al., 2006) , we tested six PPMO and found one of them (5UP1), designed to target the 5 terminal region of the PRRSV genome, to be a highly effective inhibitor of PRRSV replication in a sequence-specific and dose-dependent manner. Confirmation of the CPE observations and PRRSV yield titration was obtained by IFA on CRL11171 cells after virus inoculation and PPMO treatment (Fig. 2B ). demonstrated that PPMO generated little cytotoxicity in both CRL11171 and PAM cells, further indicating that the suppression of virus replication observed in the antiviral experiments above was due to sequence-specific effects. Treatment of cells with PPMO 5UP2 or 5HP led to suppression of PRRSV replication of all North American strains, producing virus yields not detectable (ND) in this assay.
cord-284655-zemns7wd	2015	Previous studies show that a recombinant modified vaccinia Ankara (MVA) virus expressing VP2 of AHSV serotype 4 (MVA-VP2) induced virus neutralising antibodies in horses and protected interferon alpha receptor gene knock-out mice (IFNAR −/−) against challenge. Follow up experiments indicated that passive transfer of antiserum, from MVA-VP2 immune donors to recipient mice 1 h before challenge, conferred complete clinical protection and significantly reduced viraemia. In this paper, follow-up studies investigating the relative contribution of humoral and cell-mediated immunity to the protection conferred by MVA-VP2 vaccination, using passive immunisation of naïve recipient IFNAR À/À mice with splenocytes or antiserum from MVA-VP2 vaccinated mice, are described. Vaccination of mice with a modified Vaccinia Ankara (MVA) virus expressing the African horse sickness virus (AHSV) capsid protein VP2 induces virus neutralising antibodies that confer protection against AHSV upon passive immunisation
cord-285505-8norumv6	2014	The focus of John''s presentation was on the research conducted in his own and his collaborators'' laboratories that ultimately led to the invention of three compounds which were discovered to have antiviral activity against human cytomegalovirus (HCMV) and which later entered clinical trials: BDCRB pyranoside (GW275175X) (Phase I), maribavir (Phases I, II and III) and cyclopropavir (Phase I). In monotherapy studies after oral dosing with TDF (300 mg) and TAF (25 mg), the plasma TFV AUC is reduced from 1920 to 268 ng.h/ml respectively whereas the reduction in HIV load from baseline is improved, from log 10 0.97 to log 10 1.46 copies/ml, respectively, reflecting the more efficient delivery of TAF to target cells and tissues. David Margolis, University of North Carolina, NC, USA In HIV-infected patients, there is a long-lasting reservoir of HIV in the form of integrated viral DNA in resting CD4+ memory cells of the host immune system.
cord-285856-0sw3wt1i	2009	We here report on the chemical synthesis, anti-influenza virus activity and structure-activity relationship of novel glycopeptide compounds carrying a hydrophobic side chain on an aglycoristocetin backbone ( Fig. 1) . b HPLC conditions: instrument: Waters 600 with UV230nm detection; column: Lichrospher RP-8 (4 mm × 250 mm; 10 m); injection volume: 20 l (corresponding to 2 g compound); solvents: Table 2 , several asymmetric squaric diamides derived from aglycoristocetin exerted marked activity against influenza virus, the most potent compounds being the phenylbenzyl derivative 8e [average antiviral EC 50 : 0.4 M; selectivity index (SI), defined as the ratio of MCC to EC 50 : 50]; the hexanol deriva-tive 8a (EC 50 : 1 M; SI: 14) and the naphthyl derivative 8f (EC 50 : 1.4 M; SI: 10). With regard to the antiviral mode of action, time-of-addition studies suggested that 8e blocks the viral entry process, since optimal anti-influenza virus activity was obtained when the compound was added to MDCK cells 30 min prior to or simultaneously with virus infection.
cord-286103-cgky6ar6	2006	In this study, we adopted RNA interference (RNAi) strategy and examined whether small interfering RNAs (siRNAs) can be used to inhibit replication of MeV and SSPE virus. We report here that siRNAs targeted against L mRNA of MeV, either synthetic siRNAs or those generated by pcPUR + U6i-based expression plasmids, effectively and specifically inhibited replication of both MeV and SSPE virus without exhibiting any cytotoxic effect. We report here that siRNAs targeted against L mRNA of MeV, either synthetic ones or those generated by pcPUR + U6i-based expression plasmids, effectively inhibit replication of both MeV and SSPE virus. Indeed, we demonstrated in the present study that siRNAs targeted against selected portions of L mRNA of MeV, especially MV-L2 -L4 and -L5, either synthetic siRNAs or those expressed by pcPUR + U6i-based plasmids, effectively inhibited replication of both MeV and SSPE virus (Figs.
cord-286831-ni7qfjk9	2008	Following this, 0.09 mL of diluted virus suspension of PEDV containing CCID 50 (50% cell culture infective dose) of the virus stock to produce a appropriate cytopathic effects within 2 days after infection and 0.01 mL of medium supplemented with typsin-EDTA containing an appropriate concentration of the compounds were added. Current antiviral drugs, natural compounds and flavonoids were further studied for their inhibitory effects on replication of the PEDV and cytotoxicity in Vero cells, among which ribavirin, tannic acid, coumarin and interferon-␣ exhibited the activities with IC 50 of 4.1, 47.4, 9 g/mL and 0.52 unit, respectively. A similar result was obtained in control infections with treated ribavirin (Fig. 1 ), but antiviral activity was shown to be lower than that of Q7R. Trials of ribavirin in this study showed that the drug had favorable effects on antiviral activity in Vero cells infected with PEDV.
cord-288146-xqxznv1r	2009	title: Efficient induction of cytotoxic T lymphocytes specific for severe acute respiratory syndrome (SARS)-associated coronavirus by immunization with surface-linked liposomal peptides derived from a non-structural polyprotein 1a As shown in Fig. 2 , significant numbers of IFN-␥-producing CD8 + T cells (p < 0.01) were detected in mice immunized with syngeneic cells pulsed with each of nine pp1aderived peptides including pp1a-2187, -2207, -2340, -2546, -2755, -2990, -3444, -3687, and -3709 , suggesting that these nine peptides may be HLA-A*0201-restricted CTL epitopes derived from SARS-CoV pp1a protein. After HHD mice were immunized once with one of the nine liposomal peptides, spleen cells of them were prepared, stimulated with a relevant synthetic peptide, and stained for their expression of surface CD8 and intracellular IFN-␥. In summary, we have identified seven HLA-A*0201-restricted CTL epitopes derived from pp1a protein of SARS-CoV using computational algorithms, HLA-A*0201 transgenic mice and the surface-linked liposomal peptide.
cord-288337-sw7xjpbr	2006	Five microliters of influenza virus suspension (500 ng protein) in 50 mM sodium acetate buffer (pH 5.5) containing two-fold serial dilution of the EBN extracts was stored at 37 • C for 30 min and then incubated with 5 l of 4 mM 2 -(4-methylumbelliferyl)-␣-d-N-acetylneuraminic acid (4-MU-Neu5Ac) (Sigma-Aldrich, St. Louis, MO) at 37 • C for 30 min. In order to check the reaction of EBN extract with influenza viruses, we used the human influenza virus strain A/Aichi/2/68 (H3N2), which bound to both sialyl ␣2-3 and ␣2-6 galactose linkages in salylglycoproteins and sialylglycolipids, and carried out an SDS-PAGE Western blotting assay to analyze the glycoprotein molecules. As shown in Fig. 2A , in case of no treatment with the pancreatic enzyme, neither the EBN extract from S1 nor that from S2 inhibited the hemagglutination of influenza A virus (strain A/Aichi/2/68) to human type O erythrocytes.
cord-291143-nkv1h3uh	2020	title: Conserved T-cell epitopes of respiratory syncytial virus (RSV) delivered by recombinant live attenuated influenza vaccine viruses efficiently induce RSV-specific lung-localized memory T cells and augment influenza-specific resident memory T-cell responses Surprisingly, the CD69(+)CD103(+) influenza-specific CD8 Tem responses were augmented by the addition of RSV epitopes, possibly as a result of the local microenvironment formed by the RSV-specific memory T cells differentiating to T(RM) in the lungs of mice immunized with LAIV-RSV chimeric viruses. demonstrated that a booster immunization with M2 82 RSV epitope, delivered directly to the lungs by a recombinant influenza virus expressing this epitope, generated RSV-specific lung-localized memory CD8 T cells, which were associated with reduced immunopathology following RSV challenge (Schmidt et al., 2018) . However, significant levels of CD4 Tem cells, expressing both CD69 and CD103 markers associated with tissue residence, were identified in the lungs of mice immunized with either of the LAIV-RSV vaccine candidates (Fig.3B ).
cord-292830-gcfx1095	2018	Here, we reviewed all approved, investigational and experimental antiviral agents, which are safe in man, and identified 59 compounds that target at least three viral diseases. Here, we hypothesised that some of the identified safe-in-human BSAs could possess novel antiviral activities and, therefore, could be used for treatment of many different viral infections. Fig. 1 shows BSAs and other approved antiviral drugs linked to viral and host targets through viruses they inhibit. Thus, we tested several known BSA agents against (−)ssRNA, (+) ssRNA, ssRNA-RT and dsDNA viruses and identified novel activities for dalbavancin against EV1, ezetimibe against ZIKV and HIV-1, as well as azacitidine, cyclosporine, minocycline, oritavancin and ritonavir against RVFV. We identified novel antiviral activities for dalbavancin (against EV1), ezetimibe (against HIV-1 and ZIKV), azacitidine, cyclosporine, minocycline, oritavancin and ritonavir (against RVFV) (Fig. 4) .
cord-295421-zy517zwr	2014	title: Swine interferon-induced transmembrane protein, sIFITM3, inhibits foot-and-mouth disease virus infection in vitro and in vivo Ectopic expression of sIFITM3 significantly inhibited non-enveloped foot-and-mouth disease virus (FMDV) infection in BHK-21 cells. Furthermore, sIFITM3 blocked FMDV infection at early steps in the virus life cycle by disrupting viral attachment to the host cell surface. Ectopic expression of sIFITM3 inhibited infection of non-enveloped FMDV in baby hamster kidney (BHK-21) cells by disrupting viral attachment, and this differs from human IFITM3 restriction on enveloped viruses. Two days post infection of the cell lines with viruses, plaque assay showed that BHK-sIFITM3 was less susceptible to infection by type O FMDV strains O/ES/ 2001, O/GD/2010, and O/AH/2010 than the control BHK-eGFP, and reduced plaque formation numbers by over 11-to 24-fold (Fig. 2C ). In addition, post infection with type Asia 1 FMDV Asia 1/JS/2005, the plaque formation number was reduced to over 13fold in BHK-sIFITM3 cells (Fig. 2C) .
cord-295470-mua0qvst	2020	In this study, we showed that both nitazoxanide and mizoribine had antiviral activity in F81 cells infected with different strains of FCV and also demonstrated a synergistic effect between the two drugs. (C and D) Virus TCID 50 values were calculated to determine the combined effect of different concentrations of NTZ (0-2.5 μM) and MZR (0-20 μM) on FCV. NTZ and MZR not only had antiviral efficacy against the FCV CH-JL2 strain, but the TCID 50 values of the CH-JL1, CH-JL3, CH-JL4 and CH-SH strains were also significantly different after drug treatment (p < 0.0332) (Figure 2A ). After oral NTZ treatment, either on -1 dpi or 3 dpi, levels of FCV in the trachea and lungs were significantly lower than in the control group (p < 0.0002) ( Figure 4F ). NTZ was shown to reduce viral load in the trachea and lungs and still had a therapeutic effect on FCV-infected cats when administered at 3 dpi.
cord-297072-f5lmstyn	2012	title: A hexapeptide of the receptor-binding domain of SARS corona virus spike protein blocks viral entry into host cells via the human receptor ACE2 Peptide (438)YKYRYL(443) is part of the receptor-binding domain (RBD) of the spike protein of SARS-CoV. The interaction of SARS-CoV with its receptor ACE2 is an attractive drug target as epitopes of the RBD on the spike protein may serve as leads for the design of effective entry inhibitors (Du et al., 2009) . This method allows the determination of the binding specificity, as Table 2 Synthetic peptide library of fourteen 6mer peptides comprising RBD-residues N435-E452 and A471-S500 of SARS-CoV spike protein. We found a hexapeptide in the receptor-binding domain (RBD) of the S protein of SARS-CoV that carries a significant portion of the binding affinity of the virus to the human cell. Inhibition of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) infectivity by peptides analogous to the viral spike protein
cord-297398-40bshqly	2019	To compare antiviral potencies, PK-15 cells were infected with TGEV at an MOI of 0.1 and then treated with DMSO or compounds at various concentrations, and the virus yield in the supernatants was determined at 36 hpi ( Fig. 1C and E). To explore whether the antiviral activity of A9 is affected by the cell type or virus-to-cell ratio, viral inhibition assays were performed in epithelial and fibroblast derived cell types and at various MOIs. Both PK-15 and ST cells were treated with A9 or vehicle control (DMSO) and infected with TGEV at an MOI of 0.01, 0.1, or 1. To explore whether A9 affects TGEV replication by inhibiting downstream mediators of the p38 or JNK MAPK pathways, we treated TGEV-infected PK-15 cells with the specific inhibitor BIRB796 or DB07268 and determined the toxicity of inhibitors in PK-15 cells using the MTT assay.
cord-297531-et1sli23	2017	Our current investigation found a mAb, m27f that recognizes a new continuous epitope (residues 292 to 297) within the pro-fusion domain of HSV and possesses a high level of virus-neutralizing activity. Briefly, virusantibody mixture was incubated for 1 h at 4°C before inoculating over the Vero cells (pre-attachment), while prechilled (4°C for 15 min) Vero cells were infected with HSV-1 or HSV-2 (100 pfu/well) at 4°C for 1 h to allow virus adsorption before serial dilutions of antibodies were added (post-attachment). After 2 h of adsorption at 37°C, the virus inoculum was removed and cells were washed with PBS twice then incubated in DMEM containing 2% FBS in the presence of antibodies, m27f (500 μg/ml) and 21C11 (500 μg/ml), mouse IgG (500 μg/ml), or medium alone as a control. As shown in Fig. 4A , m27f completely inhibited cell-to-cell spread of both HSV-1 and HSV-2, as evidenced by observing the limited fluorescence caused by virus infection.
cord-298166-045evk7g	2018	As no preventive vaccines or antiviral drugs against these two re-emerging pathogens are available, we evaluated whether the molecular tweezer CLR01 may inhibit EBOV and ZIKV infection. The tweezer inhibited infection of epidemic ZIKV strains in cells derived from the anogenital tract and the central nervous system, and remained antivirally active in the presence of semen, saliva, urine and cerebrospinal fluid. Methods describing the effect of CLR01 on pseudotyped lentiviral particles (2.3.), Ebola virus infection (2.4.), the detection of ZIKV infection by a colorimetric MTT assay (2.5.) or by cell-based ZIKV immunodetection assay (2.6.), flow cytometry (2.7.) and confocal microscopy (2.8.) as well as the RNA release assay (2.9.) and the antiviral activity of CLR01 in body fluids (2.10) can be found in the supplement.
cord-298938-xemarhlv	2004	title: Apoptosis induced by a cytopathic hepatitis A virus is dependent on caspase activation following ribosomal RNA degradation but occurs in the absence of 2′–5′ oligoadenylate synthetase We have presented previously evidence that the cytopathogenic 18f strain of hepatitis A virus (HAV) induced degradation of ribosomal RNA (rRNA) in infected cells [Arch. Based on the pattern of rRNA degradation in intact ribosomes, we suggested that the 18f virus activates the interferon (IFN) controlled 2 -5 oligoadenylic acid-dependent RNase L pathway (for recent reviews, see Stark et al., 1998; Barber, 2001; Sen, 2001) . First, the level of IFN, 2 -5 OAS and RNase L mRNAs were investigated by RT-PCR to determine if any of these RNAs were induced following virus infection (Fig. 8) . RT-PCR amplification of selected cellular and viral mRNAs. Two microgram of RNA isolated from virus infected, IFN-␤, or dsRNA treated cells were reverse transcribed in a volume of 20 l using oligo(dT) 15 as primer as described in Section 2.
cord-299189-59d4aojh	2013	title: Transmissible gastroenteritis virus: Identification of M protein-binding peptide ligands with antiviral and diagnostic potential In this study, the M protein of transmissible gastroenteritis virus (TGEV) was used to biopan a 12-mer phage display random peptide library. Plaque-reduction assays revealed that pepTGEV-M7 was able to prevent TGEV infection in vitro (p < 0.01) following pretreatment of the virus with the peptide. coli (Fig. 1) for use in biopanning the phage display library to identify peptides that bind the M protein of TGEV. Ten different TGEV-M protein-reactive phages were identified by ELISA, when rTGEV-M was used as the coating antigen (Fig. 2a) . 100TCID50 TGEV virus was pre-incubated with 2-fold, serially-diluted (500-31.25 lg/ml) peptide (pepTGEV-M7) then added to ST cells for 48 h. Bacterial expression of antigenic sites A and D in the spike protein of transmissible gastroenteritis virus and evaluation of their inhibitory effects on viral infection
cord-299224-7jgmxtzd	2020	In this study, using dimeric amidobenzimidazole (diABZI), a newly discovered synthetic small molecule STING receptor agonist with much higher potency than CDNs, we found that activation of STING elicits potent antiviral effects against parainfluenza virus type 3 (PIV3) and human rhinovirus 16 (HRV16), two representative respiratory viral pathogens. In both PIV3-infected Hep2 and H1-HeLa cells, BX795 completely abolished the anti-PIV3 activity of diABZI, whereas no significant impairment was observed with CQ treatment, J o u r n a l P r e -p r o o f suggesting that the activation of immune responses via TBK1 plays a dominant role in STING-mediated anti-PIV3 activity (Figs. In this study, the diABZI STING agonist demonstrated potent antiviral activity against multiple respiratory RNA viruses, represented by PIV3 and HRV16, which broadly affect human health and have no effective treatment or vaccine.
cord-299964-sn5o3ugb	2018	Furthermore, 3C(pro) inhibited the ubiquitination of retinoic acid-inducible gene I (RIG-I), TANK-binding kinase 1 (TBK1), and TNF receptor-associated factor 3 (TRAF3), thereby blocking the expression of interferon (IFN)-β and IFN stimulated gene 54 (ISG54) mRNAs. A detailed analysis revealed that mutations (H48A, C160A, or H48A/C160A) that ablate the Cys and His residues of 3C(pro) abrogated its deubiquitinating activity and the ability of 3C(pro) to block IFN-β induction. To determine whether SVV can evade innate immune response by inhibiting the host ubiquitination, HEK293T cells were transfected with FLAG-tagged VP1, VP2, 2AB, 2B, 2C, 3D, 3C plasmids along with HA-Ub plasmid. As shown in Fig. 1A , expression of 3C pro resulted in a dose-dependent reduction of the level of ubiquitinated cellular proteins compared with that in the empty vector-transfected cells. Taken together, these results indicate that SVV and 3C pro inhibit the ubiquitination of RIG-I, TBK1, and TRAF3 in a DUB-dependent manner.
cord-300117-rlpzejjt	2020	In the case of human-infecting coronaviruses such as HCoV-OC43 (Le Coupanec et al., 2015) , MERS-CoV (Millet and Whittaker, 2014) , and HKU1 (Chan et al., 2008) the spike protein has been demonstrated to be cleaved at an S1/S2 cleavage site (Fig. 2) generating the S1 and S2 subunits. The furin-like S2′ cleavage site at KR↓SF with P1 and P2 basic residues and a P2′ hydrophobic Phe (Seidah and Prat, 2012) , downstream of the IFP is identical between the 2019-nCoV and SARS-CoV (Fig. 2) . However, in the other less pathogenic circulating human CoV, the S2′ cleavage site only exhibits a monobasic R↓S sequence (Fig. 2) with no basic residues at either P2 and/or P4 needed to allow furin cleavage, suggesting a less efficient cleavage or higher restriction at the entry step depending on the cognate proteases expressed by target cells.
cord-308110-cco3aq4n	2020	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. Considering the fact that the regulation of excessive immune activation is required to treat COVID-19 patients at the late stage of the disease, CVC should be further pursued for its potential in the treatment of SARS-CoV-2 infection. Since not only the inhibition of viral replication but also the control of excessive immune activation is mandatory to save COVID-19 patients at the late stage of the disease, CVC should be further pursued for its potential in the treatment of SARS-CoV-2 infection.
cord-310469-v4p01rze	2007	Thus, in an effort to characterize antiviral agents that could attenuate infections caused by OROV, CARV, GMAV, GROV and TCMV, we tested the in vitro and in vivo actions of IFN-␣ on these viruses. However, treatment of CARV-, GMAV-or TCMV-infected mice with IFN-␣A did not result in an increase in survival or prolongation of the mean time to death and did not prevent virus replication in the brain of animals (Table 2 and Fig. 3, respectively) . Treatment with IFN-␣A initiated 24 h after mice infection by GROV was unable to inhibit either the death of animals or the viral replication in the brain (Table 3 and Fig. 5 , respectively). In vitro and in vivo results showed that IFN-␣ was able to prevent viral replication in a limited manner, exerting antiviral effect only when administrated early and in high doses, suggesting that OROV, CARV, GMAV, GROV and TCMV present some escape mechanism from antiviral actions of the IFN-␣.
cord-312688-12san3m7	2016	title: Filovirus proteins for antiviral drug discovery: A structure/function analysis of surface glycoproteins and virus entry After replication of the viral genome and RNA transcription, nascent viral particles are assembled in a process mediated by the matrix protein VP40, and virus budding occurs at the cell surface membrane in a process that involves hijacking the host ESCRT machinery (Hartlieb and Weissenhorn, 2006; Noda et al., 2006) . However, no direct interaction between both molecules has been demonstrated yet, and recent studies suggest that a 5 b 1 -integrin is not required for GP-mediated binding of internalization, but rather is a positive regulator of cathepsins, which play an important role in processing GP 1 into its fusion-competent form within the endosomes of infected cells (Schornberg et al., 2009) . After attachment mediated by interaction between the filovirus surface protein GP 1,2 (PDB: 3CSY) and various attachment factors, the complex is internalized and routed to the endosome, where GP 1,2 is processed to trigger fusion of viral and host membranes.
cord-312965-5hcb15xc	2011	A structural determined heteropolytungstate, [K(4)(H(2)O)(8)Cl][K(4)(H(2)O)(4)PTi(2)W(10)O(40)]·NH(2)OH 1, has been synthesized and evaluated for in vitro antiviral activities against hepatitis B (HBV) and SARS virus. The levels of HBsAg, HBeAg and extracellular HBV DNA in the medium were measured at different time points in the control group, ADV group, and compound 1 group, respectively, as shown in Fig. 4 . The levels of HBeAg, HBsAg and extracellular HBV DNA decreased with time in HepG 2.2.15 cells, indicating that the anti-HBV activity of compound 1 is time-dependent (P < 0.01). To characterize the anti-HBV mechanism of compound 1, the amounts of intracellular viral pgRNA and DNA were measured in the control group, ADV group, and compound 1 group at different concentrations, respectively, at day 5, as shown in Fig. 5 . to the cytotoxic results, compound 1 was diluted at five non-toxic concentrations (31.2, 15.6, 7.8, 3.9 , and 1.95 lM) and the anti-SARS virus activity was checked with MTT assay.
cord-314833-6fue84x6	2014	
cord-315524-vgdjpjkj	2020	We identified gemcitabine, a widely used anti-cancer drug, as a potent inhibitor of rotavirus infection. Supplementation of UTP or uridine largely abolished the anti-rotavirus activity of gemcitabine, suggesting its function through inhibition of pyrimidine biosynthesis pathway. Furthermore, immunofluorescent staining of viral capsid protein (VP6) showed significant reduction of the number of infected Caco2 cells by gemcitabine treatment (Fig. 1F, 1G, Supplementary Fig. S2 ). Our previous studies have evaluated the effects of the nucleoside analog ribavirin and mycophenolic acid (MPA), and the antiviral cytokine interferon alpha (IFN-α) on rotavirus in cell culture models. We have previously established modeling of rotavirus infection in intestinal organoids, which allows the study of virus-host interactions and assessment of antiviral drugs (Yin et al., 2015a; Yin et al., 2018a; Yin et al., 2018b; Yin et al., 2016) . Gemcitabine, a widely used anti-cancer drug, has potent antiviral activity against rotavirus infection Gemcitabine exerts its anti-rotavirus effect through inhibiting pyrimidine biosynthesis pathway
cord-316503-wtmmewiz	2012	Phosphorodiamidate morpholino oligomers (PMOs) are synthetic antisense oligonucleotide analogs that are designed to interfere with translational processes by forming base-pair duplexes with specific RNA sequences. Peptide conjugated PMOs (PPMOs; Fig. 2 ), which include positively charged amino acid residues such as arginine, have been viewed as particularly promising transporters and have shown efficacy in multiple in vivo models of viral infection (Enterlein et al., 2006; Paessler et al., 2008; Stein, 2008; Swenson et al., 2009) . While PPMOs are efficacious in multiple in vivo models of viral infections, PPMOs are more poorly tolerated in vivo compared to neutral-charge PMOs. In mice, dose-dependent reductions in weight, behavioral alterations, and mild liver histopathology were observed following repeat administration of 200-300 lg doses of a PMO conjugated to an arginine-rich peptide (Deas et al., 2007) .
cord-316624-bqaqhp3m	2009	Virus plaque-reduction assays, PCR and RT-PCR analysis indicated that both drugs inhibited cell infection by PrV. Briefly, FITC-conjugated Annexin V (50 l/well) and propidium iodide, PI (50 l/well) were added the cells infected by drug-treated viruses, or the virus-infected cells treated with LiCl in 24-well plates and incubated at room temperature for 15 min in the dark prior to fluorescence observation. At the maximum non-toxic concentration of the drugs, the inhibition rate of LiCl and DG for PrV infection in cell culture reached 100% (Fig. 4) . The effect of both drugs on PrV-infected cells was analyzed using plaque-reduction assays. As shown in Fig. 9 , the maximum nontoxic concentration of drugs had an inhibitory activity against PrV-induced cell apoptosis. It is possible that the observed anti-apoptotic effect of DG and LiCl during PRV infection is indirect and due to the reduced virus replication caused by the drugs.
cord-316996-8yimrpaz	2013	DAS181 is an inhaled bacterial sialidase which functions by removing sialic acid (Sia) from the surface of epithelial cells, preventing attachment and subsequent infection by respiratory viruses that utilize Sia as a receptor. DAS181 is the first antiviral compound in Phase II development that functions by blocking this pathogen-host interaction, by destroying the influenza host-cell receptor, sialic acid (Sia), on the surface of respiratory epithelial cells. In this paper, we provide background information on Sia and sialidases; discuss the potential role of bacterial sialidases as antiviral agents; review the in vitro and Phase II evaluation of DAS181 for the treatment of influenza; and note evidence that the drug would also be useful against parainfluenza virus infections. Even though influenza virus has been the most well characterized of the pathogens studied, it must be noted that other viruses, including cytomegalovirus (Taylor and Cooper, 1989) , rhinovirus 87 (Blomqvist et al., 2002) , mumps Urabe AM9 (ReyesLeyva et al., 2007) and the paramyxoviruses all utilize Sia (Suzuki et al., 2001) (Paulson et al., 1979) , suggesting that sialidase treatment may potentially be useful for these infections.
cord-328468-bwn4bmf5	2010	We have recently demonstrated the antibacterial activity of two types of AMPs, the thrombin-induced human platelet-derived antimicrobial peptides (PD) and the arginine-tryptophan (RW) repeat peptides, against aerobic bacterial contaminants encountered in blood products (Mohan et al., 2009a) . PD3, PD4 and RW3 peptides were each incubated with the virus inoculum for 2 h at room temperature and tested for antiviral activity by performing the plaque assay as described in the pre-infection experiment. Analysis of the post virus-binding experiment revealed that none of the PD or RW peptides were able to inhibit virus infection as there was no significant difference in the viral titers between the test and control groups (Fig. 2) . Human plasma samples spiked with 10 2 pfu of VV-WR virus were incubated with PD3, PD4 and RW3 peptides individually for 2 h and tested for antiviral activity by infecting B-SC-1 cells and measuring virus titer by performing the plaque assay as described in the pre-infection experiment.
cord-329494-cdn52epy	2009	The efficacy of this Z2-siRNA against JUNV was also demonstrated in virus-infected cells, by testing infectious virus plaque formation (92.8% JUNV yield reduction), viral RNA level or antigen expression, as well as in cells transfected with Z-specific reporter plasmids (91% reduction in expression of Z-EGFP fusion protein). (E) Expression of viral antigens in Vero cells transfected with Z2-siRNA or X-siRNA and infected with JUNV was detected by immunofluorescence assay using a rabbit anti-JUNV polyclonal serum. The efficacy of this agent against JUNV was also demonstrated in virus-infected cells by testing infectious virus plaque formation, viral RNA or antigen expression, as well as in cells transfected with Z-specific reporter plasmids. The present study represents the first report of virus inhibition mediated by RNA interference for a New World arenavirus, a group in the family including four agents of severe viral hemorrhagic fevers in South America (JUNV, Machupo, Sabiá and Guanarito viruses).
cord-329642-5t8yuq4v	2013	Several agents that significantly inhibit FCoV replication in vitro have been identified (Balzarini et al., 2006; Barlough and Shacklett, 1994; Hsieh et al., 2010; Kim et al., 2012; Takano et al., 2008) ; however, whether or not these agents exhibit a therapeutic effect in cats with FIP has not been investigated. The effect of chloroquine on FIPV infection in fcwf-4 cells and SPF cat-derived monocytes was investigated. In monocytes inoculated with a mixture of FIPV and MAb 6-4-2, IL-1b, TNF-a and IL-6 mRNA expression levels were significantly lower in the Pre/Post treatment group than in the None group (Fig. 3B) . The influence of chloroquine on cytokine mRNA and FCoV N gene expressions was investigated in monocytes from cats with FIP. IL-1b, TNF-a, and IL-6 mRNA expression levels of PBMC in FIPV-infected cats treated with chloroquine. In this study, chloroquine significantly inhibited inflammatory cytokine mRNA expression levels in FIPV-infected monocytes.
cord-329959-4yecwdlo	2017	Here we show that a clinically available alcohol-aversive drug, disulfiram, can inhibit the papain-like proteases (PL(pro)s) of MERS-CoV and SARS-CoV. The phenomenon of slow-binding inhibition and the irrecoverability of enzyme activity after removing unbound disulfiram indicate covalent inactivation of SARS-CoV PL(pro) by disulfiram, while synergistic inhibition of MERS-CoV PL(pro) by disulfiram and 6-thioguanine or mycophenolic acid implies the potential for combination treatments using these three clinically available drugs. For the inactivation studies, SARS-CoV PL pro (0.05 μM in 20 mM phosphate buffer, pH 6.5) was incubated with different concentrations of disulfiram and peptide substrate, and enzymatic activity was traced for 5 min. On the other hand, the results of kinetic assays, continued inactivation after the removal of disulfiram, reactivation by reductant, and the phenomenon of slow-binding inhibition suggest that disulfiram may act at the active site of SARS-CoV PL pro , forming a covalent adduct with residue Cys112.
cord-332952-d5l60cgc	2018	Typical of an emerging zoonosis, Middle East respiratory syndrome coronavirus (MERS-CoV) has an animal reservoir, i.e. dromedary camels in which the virus causes little to no disease (Mohd et al., 2016) . For example, studies of respiratory pathogens (Yu et al., 2007; Tran et al., 2012; Thompson et al., 2013) and MERS-CoV conducted in the Middle East (Assiri et al., 2013; Oboho et al., 2015; Hunter et al., 2016; Balkhy et al., 2016) and the Republic of Korea (Bin et al., 2016; Kim et al., 2016a Kim et al., , 2016b Nam et al., 2017) illustrate that aerosol-generating procedures and non-invasive ventilation, combined with inappropriate infection prevention and control practices and lack of adherence to standard practices had an important role in facilitating human-to-human transmission in health care settings. The critical care response to a hospital outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) infection: an observational study Sero-prevalence of Middle East respiratory syndrome coronavirus (MERS-CoV) specific antibodies in dromedary camels in Tabuk, Saudi Arabia
cord-336093-ic6q6ke8	2014	Abbreviations: SARS, severe acute respiratory syndrome; SARS-CoV, SARS coronavirus; nsp, nonstructural protein; N7-MTase, guanine-N7-methyltransferase; 2 0 -O-MTase, 2 0 -O-methyltransferase; AdoMet, S-adenosyl-L-methionine; AdoHcy, S-adenosyl-L-homocysteine; ATA, aurintricarboxylic acid; IC 50 , inhibitory concentration at 50% activity. A single transformed colony of the YBS40 strain containing plasmids expressing human N7-MTase (MT-Human), SARS-CoV N7-MTase (MT-SARS), N7-MTases of other coronaviruses (MT-MHV, MT-TGEV, and MT-IBV), and the pMceK294A vector as control (representing the yeast N7-MTase [MT-Yeast]), were inoculated separately into 5 ml of a basic medium (Min SD Base) lacking tryptophan and incubated at 30°C for 21-24 h until reaching a similar final cell density in the stationary phase (0.5-1.0 Â 10 8 cells/ml) (Chrebet et al., 2005) . Although AdoHcy, ATA and sinefungin, were previously reported to be inhibitors of coronavirus RNA MTases in vitro , only sinefungin significantly suppressed the growth of the MT-yeast, MT-human, and MT-SARS yeast cells (Fig. 3 ).
cord-336517-v7z62tld	2018	Further studies suggest that PEDV PL2 pro exhibits much higher DUB activity than that of SARS-and MERS-CoV PL pro s and can be inhibited by the anti-leukemia drug 6-thioguanine (6TG). Previous studies suggested that the Ubl domain was not involved in the catalytic activity of SARS-and MERS-CoV PL pro s (Chou et al., 2012; Clasman et al., 2017) . Overall, the secondary, tertiary and quaternary structures of the PEDV PL2 pro catalytic core are similar to those of SARS-and MERS-CoV PL pro s, even though their sequence identity is only 22-25% (Fig. S1 ). In contrast, previous studies suggested that the binding site of 6TG for SARS-and MERS-CoV PL pro s may be near the catalytic triad''s cysteine residue due to its competitive pattern of inhibition Chou et al., 2008) . Structural and mutational analysis of the interaction between the Middle-East respiratory syndrome coronavirus (MERS-CoV) papain-like protease and human ubiquitin
cord-337645-t6py0oyw	2010	Though S protein was not solubilized by cold non-ionic detergents, this behavior was unchanged when cholesterol was depleted from viral membrane by methyl-β-cyclodextrin (MβCD) and the protein did not comigrate with cellular DRM marker proteins in flotation analyses. A functional analysis suggests that cholesterol depletion affects a post-adsorption step in the virus entry process that requires membrane rearrangements. As cholesterol depletion from TGE virions results in a reduction of viral infectivity (Ren et al., 2008) , we were interested to find out whether the surface protein S that mediates virus entry is localized in DRMs. For this purpose, we analyzed whether the TGEV S protein is resistant to solubilization by Triton X-100 at 4 • C. This result indicates that the surface protein of TGEV is arranged in the viral envelope in a detergent-resistant way that is not affected by cholesterol depletion.
cord-348401-x2q9vyf2	2016	The MERS-CoV spike protein is a main determinant of virus entry into host cells as it mediates both binding to the DPP4 (dipeptidyl peptidase 4) receptor and fusion of the viral envelope with host cell membrane (Millet and Whittaker, 2014; Raj et al., 2013) . Immunofluorescence assay of MERS-CoV-infected Huh-7, MRC-5, and Vero-81 cells in presence of increasing concentrations of griffithsin. In all conditions, cells were infected with MERS-CoV strain EMC/2012 at an m.o.i. of 10, with griffithsin (1 mg/mL) added or not at different steps during virus entry. Because we have performed our assay using high m.o.i. and a short infection time, these results show the strong inhibitory activity of griffithsin on early steps of the MERS-CoV viral cycle. To better define which stage in the virus life cycle griffithsin acts on, we performed an infection assay using authentic MERS-CoV with griffithsin present at different times during viral entry steps (Fig. 4A) .