Antiviral activity of 5-aminolevulinic acid against variants of severe acute respiratory syndrome coronavirus 2

Abstract Background Genetic variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began to emerge in 2020 and have been spreading globally during the coronavirus disease 2019 (COVID-19) pandemic. Despite the presence of different COVID-19 vaccines, the discovery of effective antiviral therapeutics for the treatment of patients infected with SARS-CoV-2 are still urgently needed. A natural amino acid, 5-aminolevulinic acid (5-ALA), has exhibited both antiviral and anti-inflammatory activities. In a previous study, we demonstrated an in vitro antiviral effect of 5-ALA against SARS-CoV-2 infection without significant cytotoxicity. In the present study, we sought to investigate whether 5-ALA with or without sodium ferrous citrate (SFC) can inhibit in vitro both the original SARS-CoV-2 Wuhan strain and its variants, including the Alpha, Beta, Gamma and Delta strains. Methods The antiviral activity of ALA with or without SFC was determined in Vero-E6 cell. The virus inhibition was quantified by real time RT-PCR. Results Co-administration of 5-ALA and SFC inhibited the Wuhan, Alpha and Delta variants of SARS-CoV-2 with IC50 values of 235, 173 and 397 µM, respectively, and the Beta and Gamma variants with IC50 values of 1311 and 1516 µM. Conclusion Our study suggests that 5-ALA with SFC warrants accelerated clinical evaluation as an antiviral drug candidate for treating patients infected with SARS-CoV-2 variants.

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Antiviral Activity of Favipiravir (T-705) against a Broad Range of ParamyxovirusesIn Vitroand against Human Metapneumovirus in Hamsters

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00709-16 ◽

2016 ◽

Vol 60 (8) ◽

pp. 4620-4629 ◽

Cited By ~ 20

Author(s):

D. Jochmans ◽

S. van Nieuwkoop ◽

S. L. Smits ◽

J. Neyts ◽

R. A. M. Fouchier ◽

...

Keyword(s):

Antiviral Activity ◽

Measles Virus ◽

Rna Virus ◽

Antiviral Drug ◽

Specific Effect ◽

Human Metapneumovirus ◽

Drug Candidate ◽

Emerging Viruses ◽

Syncytial Virus

ABSTRACTThe clinical impact of infections with respiratory viruses belonging to the familyParamyxoviridaeargues for the development of antiviral therapies with broad-spectrum activity. Favipiravir (T-705) has demonstrated potent antiviral activity against multiple RNA virus families and is presently in clinical evaluation for the treatment of influenza. Here we demonstratein vitroactivity of T-705 against the paramyxoviruses human metapneumovirus (HMPV), respiratory syncytial virus, human parainfluenza virus, measles virus, Newcastle disease virus, and avian metapneumovirus. In addition, we demonstrate activity against HMPV in hamsters. T-705 treatment inhibited replication of all paramyxoviruses testedin vitro, with 90% effective concentration (EC90) values of 8 to 40 μM. Treatment of HMPV-challenged hamsters with T-705 at 200 mg/kg of body weight/day resulted in 100% protection from infection of the lungs. In all treated and challenged animals, viral RNA remained detectable in the respiratory tract. The observation that T-705 treatment had a significant effect on infectious viral titers, with a limited effect on viral genome titers, is in agreement with its proposed mode of action of viral mutagenesis. However, next-generation sequencing of viral genomes isolated from treated and challenged hamsters did not reveal (hyper)mutation. Polymerase activity assays revealed a specific effect of T-705 on the activity of the HMPV polymerase. With the reported antiviral activity of T-705 against a broad range of RNA virus families, this small molecule is a promising broad-range antiviral drug candidate for limiting the viral burden of paramyxoviruses and for evaluation for treatment of infections with (re)emerging viruses, such as the henipaviruses.

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GNS561 exhibits potent in vitro antiviral activity against SARS-CoV-2 through autophagy inhibition

10.1101/2020.10.06.327635 ◽

2020 ◽

Author(s):

Philippe Halfon ◽

Eloïne Bestion ◽

Keivan Zandi ◽

Julien Andreani ◽

Jean-Pierre Baudoin ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Antiviral Activity ◽

Antiviral Effect ◽

Therapeutic Strategies ◽

Multilamellar Bodies ◽

Molecule Inhibitor ◽

Lipophilic Molecule ◽

Autophagic Process ◽

Autophagy Inhibition

AbstractSince December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2/2019-nCoV) has spread quickly worldwide, with more than 29 million cases and 920,000 deaths. Interestingly, coronaviruses were found to subvert and hijack the autophagic process to allow their viral replication. One of the spotlights had been focused on the autophagy inhibitors as a target mechanism effective in the inhibition of SARS-CoV-2 infection. Consequently, chloroquine (CQ) and hydroxychloroquine (HCQ), a derivative of CQ, was suggested as the first potentially be therapeutic strategies as they are known to be autophagy inhibitors. Then, they were used as therapeutics in SARS-CoV-2 infection along with remdesivir, for which the FDA approved emergency use authorization. Here, we investigated the antiviral activity and associated mechanism of GNS561, a small basic lipophilic molecule inhibitor of late-stage autophagy, against SARS-CoV-2. Our data indicated that GNS561 showed the highest antiviral effect for two SARS-CoV-2 strains compared to CQ and remdesivir. Focusing on the autophagy mechanism, we showed that GNS561, located in LAMP2-positive lysosomes, together with SARS-CoV-2, blocked autophagy by increasing the size of LC3-II spots and the accumulation of autophagic vacuoles in the cytoplasm with the presence of multilamellar bodies characteristic of a complexed autophagy. Finally, our study revealed that the combination of GNS561 and remdesivir was associated with a strong synergistic antiviral effect against SARS-CoV-2. Overall, our study highlights GNS561 as a powerful drug in SARS-CoV-2 infection and supports that the hypothesis that autophagy inhibitors could be an alternative strategy for SARS-CoV-2 infection.

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Scientifically unproven treatments for COVID-19

Bionatura ◽

10.21931/rb/2020.05.04.3 ◽

2020 ◽

Vol 5 (4) ◽

pp. 1295-1296

Author(s):

Martín S. Marcial-Coba

Keyword(s):

Public Health ◽

Severe Acute Respiratory Syndrome ◽

Antiviral Activity ◽

Antiviral Drug ◽

Public Health Emergency ◽

Limited Information ◽

Safety And Efficacy ◽

Robust System ◽

First Time

Detected for the first time in late December 2019, a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the causative agent of an international outbreak of coronavirus disease 2019 (COVID-19). In late August 2020, approx. 24 000 000 cases, including 815 038 deaths, have been confirmed worldwide1. The WHO declared the outbreak of COVID-19 as a Public Health Emergency of International Concern, and it has been proposed that its spread may be interrupted by early detection, isolation, the implementation of a robust system to trace contacts, and a prompt treatment2. Nevertheless, there has not yet been any vaccine or effective treatment that has received approval3. Despite this, the FDA has recently issued an emergency use authorization for the investigational antiviral drug Remdesivir to treat COVID-19 in patients with severe disease4. Although there is still limited information regarding the safety and efficacy of this novel prodrug, it has shown potent in vitro antiviral activity against SARS-CoV-2 isolates, and therapeutic efficacy in animal models5.

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In Vitro Evaluation of the Antiviral Activity of Methylene Blue Alone or in Combination against SARS-CoV-2

Journal of Clinical Medicine ◽

10.3390/jcm10143007 ◽

2021 ◽

Vol 10 (14) ◽

pp. 3007

Author(s):

Mathieu Gendrot ◽

Priscilla Jardot ◽

Océane Delandre ◽

Manon Boxberger ◽

Julien Andreani ◽

...

Keyword(s):

Methylene Blue ◽

Antiviral Activity ◽

Viral Entry ◽

Low Cost ◽

Antiviral Drug ◽

Effective Concentration ◽

Rt Pcr ◽

Post Entry ◽

Median Effective Concentration

A new severe acute respiratory syndrome coronavirus (SARS-CoV-2) causing coronavirus diseases 2019 (COVID-19), which emerged in Wuhan, China in December 2019, has spread worldwide. Currently, very few treatments are officially recommended against SARS-CoV-2. Identifying effective, low-cost antiviral drugs with limited side effects that are affordable immediately is urgently needed. Methylene blue, a synthesized thiazine dye, may be a potential antiviral drug. Antiviral activity of methylene blue used alone or in combination with several antimalarial drugs or remdesivir was assessed against infected Vero E6 cells infected with two clinically isolated SARS-CoV-2 strains (IHUMI-3 and IHUMI-6). Effects both on viral entry in the cell and on post-entry were also investigated. After 48 h post-infection, the viral replication was estimated by RT-PCR. The median effective concentration (EC50) and 90% effective concentration (EC90) of methylene blue against IHUMI-3 were 0.41 ± 0.34 µM and 1.85 ± 1.41 µM, respectively; 1.06 ± 0.46 µM and 5.68 ± 1.83 µM against IHUMI-6. Methylene blue interacted at both entry and post-entry stages of SARS-CoV-2 infection in Vero E6 cells as retrieved for hydroxychloroquine. The effects of methylene blue were additive with those of quinine, mefloquine and pyronaridine. The combinations of methylene blue with chloroquine, hydroxychloroquine, desethylamodiaquine, piperaquine, lumefantrine, ferroquine, dihydroartemisinin and remdesivir were antagonist. These results support the potential interest of methylene blue to treat COVID-19.

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Modeling of SARS-CoV-2 Treatment Effects for Informed Drug Repurposing

Frontiers in Pharmacology ◽

10.3389/fphar.2021.625678 ◽

2021 ◽

Vol 12 ◽

Author(s):

Charlotte Kern ◽

Verena Schöning ◽

Carlos Chaccour ◽

Felix Hammann

Keyword(s):

Drug Repurposing ◽

Antiviral Effect ◽

Drug Candidate ◽

Appreciable Effect ◽

Viral Kinetics ◽

Future Drug ◽

Dosing Regimens ◽

Clinical Trial Results

Several repurposed drugs are currently under investigation in the fight against coronavirus disease 2019 (COVID-19). Candidates are often selected solely by their effective concentrations in vitro, an approach that has largely not lived up to expectations in COVID-19. Cell lines used in in vitro experiments are not necessarily representative of lung tissue. Yet, even if the proposed mode of action is indeed true, viral dynamics in vivo, host response, and concentration-time profiles must also be considered. Here we address the latter issue and describe a model of human SARS-CoV-2 viral kinetics with acquired immune response to investigate the dynamic impact of timing and dosing regimens of hydroxychloroquine, lopinavir/ritonavir, ivermectin, artemisinin, and nitazoxanide. We observed greatest benefits when treatments were given immediately at the time of diagnosis. Even interventions with minor antiviral effect may reduce host exposure if timed correctly. Ivermectin seems to be at least partially effective: given on positivity, peak viral load dropped by 0.3–0.6 log units and exposure by 8.8–22.3%. The other drugs had little to no appreciable effect. Given how well previous clinical trial results for hydroxychloroquine and lopinavir/ritonavir are explained by the models presented here, similar strategies should be considered in future drug candidate prioritization efforts.

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The in vitro and in vivo potency of CT-P59 against Delta and its associated variants of SARS-CoV-2

10.1101/2021.07.23.453472 ◽

2021 ◽

Author(s):

Dong-Kyun Ryu ◽

Hye-Min Woo ◽

Bobin Kang ◽

Hanmi Noh ◽

Jong-In Kim ◽

...

Keyword(s):

Antiviral Activity ◽

Respiratory Tract ◽

Animal Studies ◽

Antiviral Effect ◽

The World ◽

Symptom Remission ◽

Challenge Experiment ◽

Reduced Activity

The Delta variant originally from India is rapidly spreading across the world and causes to resurge infections of SARS-CoV-2. We previously reported that CT-P59 presented its in vivo potency against Beta and Gamma variants, despite its reduced activity in cell experiments. Yet, it remains uncertain to exert the antiviral effect of CT-P59 on the Delta and its associated variants (L452R). To tackle this question, we carried out cell tests and animal study. CT-P59 showed reduced antiviral activity but enabled neutralization against Delta, Epsilon, and Kappa variants in cells. In line with in vitro results, the mouse challenge experiment with the Delta variant substantiated in vivo potency of CT-P59 showing symptom remission and virus abrogation in the respiratory tract. Collectively, cell and animal studies showed that CT-P59 is effective against the Delta variant infection, hinting that CT-P59 has therapeutic potency for patients infected with Delta and its associated variants.

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Repurposing Nucleoside Analogs for Human Coronaviruses

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01652-20 ◽

2020 ◽

Vol 65 (1) ◽

pp. e01652-20

Author(s):

Keivan Zandi ◽

Franck Amblard ◽

Katie Musall ◽

Jessica Downs-Bowen ◽

Ruby Kleinbard ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Antiviral Activity ◽

Rna Polymerase ◽

Nucleoside Analogs ◽

Antiviral Effect ◽

Serious Illness ◽

Human Coronaviruses

ABSTRACTCoronavirus disease 2019 (COVID-19) is a serious illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or CoV-2). Some reports claimed certain nucleoside analogs to be active against CoV-2 and thus needed confirmation. Here, we evaluated a panel of compounds and identified novel nucleoside analogs with antiviral activity against CoV-2 and HCoV-OC43 while ruling out others. Of significance, sofosbuvir demonstrated no antiviral effect against CoV-2, and its triphosphate did not inhibit CoV-2 RNA polymerase.

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Antiviral Activity of Benzoic Acid Derivative NC-5 Against Influenza A Virus and Its Neuraminidase Inhibition

International Journal of Molecular Sciences ◽

10.3390/ijms20246261 ◽

2019 ◽

Vol 20 (24) ◽

pp. 6261

Author(s):

Min Guo ◽

Jiawei Ni ◽

Jie Yu ◽

Jing Jin ◽

Lingman Ma ◽

...

Keyword(s):

Antiviral Activity ◽

Benzoic Acid ◽

Influenza A Virus ◽

Influenza A ◽

Matrix Protein ◽

Influenza Viruses ◽

Drug Candidate ◽

Dependent Manner ◽

Drug Resistant

The currently available drugs against influenza A virus primarily target neuraminidase (NA) or the matrix protein 2 (M2) ion channel. The emergence of drug-resistant viruses requires the development of new antiviral chemicals. Our study applied a cell-based approach to evaluate the antiviral activity of a series of newly synthesized benzoic acid derivatives, and 4-(2,2-Bis(hydroxymethyl)-5-oxopyrrolidin-l-yl)-3-(5-cyclohexyl-4H-1,2,4-triazol-3-yl)amino). benzoic acid, termed NC-5, was found to possess antiviral activity. NC-5 inhibited influenza A viruses A/FM/1/47 (H1N1), A/Beijing/32/92 (H3N2) and oseltamivir-resistant mutant A/FM/1/47-H275Y (H1N1-H275Y) in a dose-dependent manner. The 50% effective concentrations (EC50) for H1N1 and H1N1-H275Y were 33.6 μM and 32.8 μM, respectively, which showed that NC-5 had a great advantage over oseltamivir in drug-resistant virus infections. The 50% cytotoxic concentration (CC50) of NC-5 was greater than 640 μM. Orally administered NC-5 protected mice infected with H1N1 and H1N1-H275Y, conferring 80% and 60% survival at 100 mg/kg/d, reducing body weight loss, and alleviating virus-induced lung injury. NC-5 could suppress NP and M1 protein expression levels during the late stages of viral biosynthesis and inhibit NA activity, which may influence virus release. Our study proved that NC-5 has potent anti-influenza activity in vivo and in vitro, meaning that it could be regarded as a promising drug candidate to treat infection with influenza viruses, including oseltamivir-resistant viruses.

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β-arrestin 2 as an activator of cGAS-STING signaling and target of viral immune evasion

Nature Communications ◽

10.1038/s41467-020-19849-9 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Yihua Zhang ◽

Manman Li ◽

Liuyan Li ◽

Gui Qian ◽

Yu Wang ◽

...

Keyword(s):

Immune Evasion ◽

Cyclic Gmp ◽

Tissue Injury ◽

Antiviral Drug ◽

Drug Candidate ◽

Antiviral Immune Response ◽

Viral Immune Evasion ◽

Cellular Events ◽

Β Blocker

AbstractVirus infection may induce excessive interferon (IFN) responses that can lead to host tissue injury or even death. β-arrestin 2 regulates multiple cellular events through the G protein-coupled receptor (GPCR) signaling pathways. Here we demonstrate that β-arrestin 2 also promotes virus-induced production of IFN-β and clearance of viruses in macrophages. β-arrestin 2 interacts with cyclic GMP-AMP synthase (cGAS) and increases the binding of dsDNA to cGAS to enhance cyclic GMP-AMP (cGAMP) production and the downstream stimulator of interferon genes (STING) and innate immune responses. Mechanistically, deacetylation of β-arrestin 2 at Lys171 facilitates the activation of the cGAS–STING signaling and the production of IFN-β. In vitro, viral infection induces the degradation of β-arrestin 2 to facilitate immune evasion, while a β-blocker, carvedilol, rescues β-arrestin 2 expression to maintain the antiviral immune response. Our results thus identify a viral immune-evasion pathway via the degradation of β-arrestin 2, and also hint that carvedilol, approved for treating heart failure, can potentially be repurposed as an antiviral drug candidate.

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EPSTI1 Is Involved in IL-28A-Mediated Inhibition of HCV Infection

Mediators of Inflammation ◽

10.1155/2015/716315 ◽

2015 ◽

Vol 2015 ◽

pp. 1-13 ◽

Cited By ~ 11

Author(s):

Xianghe Meng ◽

Darong Yang ◽

Rong Yu ◽

Haizhen Zhu

Keyword(s):

Life Cycle ◽

Antiviral Activity ◽

Viral Replication ◽

Virus Replication ◽

Antiviral Effect ◽

Vital Role ◽

Hcv Infection ◽

Rnase L ◽

Interferon Treatment

It has been reported that IFN-λs inhibit HCV replication in vitro. But the mechanisms of how IL-28A conducts antiviral activity and the functions of IL-28A-induced ISGs (IFN-stimulated genes) are not fully understood. In this study, we found that IL-28A has the antiviral effect on HCV life cycle including viral replication, assembly, and release. IL-28A and IFN-αsynergistically inhibit virus replication. EPSTI1 (epithelial-stromal interaction 1), one of IL-28A-induced ISGs, plays a vital role in IL-28A-mediated antiviral activity. Furthermore, forced expression of EPSTI1 effectively inhibits HCV replication in the absence of interferon treatment, and knockdown of EPSTI1 contributes to viral enhancement. EPSTI1 can activate PKR promoter and induce several PKR-dependent genes, including IFN-β, IFIT1, OAS1, and RNase L, which is responsible for EPSTI1-mediated antiviral activity.

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