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

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.

scholarly journals GNS561 Exhibits Potent Antiviral Activity against SARS-CoV-2 through Autophagy Inhibition

Viruses ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 132
Author(s):  
Eloïne Bestion ◽  
Keivan Zandi ◽  
Sandrine Belouzard ◽  
Julien Andreani ◽  
Hubert Lepidi ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Antiviral Activity ◽  
Mouse Model ◽  
Spot Size ◽  
Viral Strain ◽  
Multilamellar Bodies ◽  
Molecule Inhibitor ◽  
Autophagy Pathway ◽  
Autophagic Process ◽  
Autophagy Inhibition

Since December 2019, SARS-CoV-2 has spread quickly worldwide, leading to more than 280 million confirmed cases, including over 5,000,000 deaths. Interestingly, coronaviruses were found to subvert and hijack autophagic process to allow their viral replication. Autophagy-modulating compounds thus rapidly emerged as an attractive strategy to fight SARS-CoV-2 infection, including the well-known chloroquine (CQ). Here, we investigated the antiviral activity and associated mechanism of GNS561/Ezurpimtrostat, a small lysosomotropic molecule inhibitor of late-stage autophagy. Interestingly, GNS561 exhibited antiviral activity of 6–40 nM depending on the viral strain considered, currently positioning it as the most powerful molecule investigated in SARS-CoV-2 infection. We then showed that GNS561 was located in lysosome-associated-membrane-protein-2-positive (LAMP2-positive) lysosomes, together with SARS-CoV-2. Moreover, GNS561 increased LC3-II spot size and caused the accumulation of autophagic vacuoles and the presence of multilamellar bodies, suggesting that GNS561 disrupted the autophagy mechanism. To confirm our findings, we used the K18-hACE2 mouse model and highlighted that GNS561 treatment led to a decline in SARS-CoV-2 virions in the lungs associated with a disruption of the autophagy pathway. Overall, our study highlights GNS561 as a powerful drug in the treatment of SARS-CoV-2 infection and supports the hypothesis that autophagy blockers could be an alternative strategy for COVID-19.

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

2022 ◽  
Vol 50 (1) ◽  
Author(s):  
Mya Myat Ngwe Tun ◽  
Takaya Sakura ◽  
Yasuteru Sakurai ◽  
Yohei Kurosaki ◽  
Daniel Ken Inaoka ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Antiviral Activity ◽  
Aminolevulinic Acid ◽  
Antiviral Drug ◽  
Antiviral Effect ◽  
Drug Candidate ◽  
Rt Pcr ◽  
Ferrous Citrate ◽  
Virus Inhibition

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.

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

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.

scholarly journals Repurposing Nucleoside Analogs for Human Coronaviruses

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.

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

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
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.

scholarly journals IFN-λ1 Displays Various Levels of Antiviral Activity In Vitro in a Select Panel of RNA Viruses

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1602
Author(s):  
Marina Plotnikova ◽  
Alexey Lozhkov ◽  
Ekaterina Romanovskaya-Romanko ◽  
Irina Baranovskaya ◽  
Mariia Sergeeva ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Rna Viruses ◽  
Antiviral Effect ◽  
Vero Cells ◽  
Genome Replication ◽  
Type I ◽  
Protective Effects ◽  
Cellular Models ◽  
Viral Genome Replication

Type III interferons (lambda IFNs) are a quite new, small family of three closely related cytokines with interferon-like activity. Attention to IFN-λ is mainly focused on direct antiviral activity in which, as with IFN-α, viral genome replication is inhibited without the participation of immune system cells. The heterodimeric receptor for lambda interferons is exposed mainly on epithelial cells, which limits its possible action on other cells, thus reducing the likelihood of developing undesirable side effects compared to type I IFN. In this study, we examined the antiviral potential of exogenous human IFN-λ1 in cellular models of viral infection. To study the protective effects of IFN-λ1, three administration schemes were used: ‘preventive’ (pretreatment); ‘preventive/therapeutic’ (pre/post); and ‘therapeutic’ (post). Three IFN-λ1 concentrations (from 10 to 500 ng/mL) were used. We have shown that human IFN-λ1 restricts SARS-CoV-2 replication in Vero cells with all three treatment schemes. In addition, we have shown a decrease in the viral loads of CHIKV and IVA with the ‘preventive’ and ‘preventive/therapeutic’ regimes. No significant antiviral effect of IFN-λ1 against AdV was detected. Our study highlights the potential for using IFN-λ as a broad-spectrum therapeutic agent against respiratory RNA viruses.

scholarly journals In vitro determination of inhibitory effects by humic substances complexing Zn and Se on SARS-CoV-2 virus replication

2021 ◽  
Author(s):  
Bernadett Palyi ◽  
Zoltan Kis ◽  
Polett Hajdrik ◽  
Noemi S Kovacs ◽  
Daniel S Veres ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Antiviral Activity ◽  
Humic Substances ◽  
Animal Feed ◽  
Antiviral Effect ◽  
Nutritional Supplement ◽  
Feed Additives ◽  
Acid Complex ◽  
Alpha Variant

Humic substances are well known human nutritional supplement materials and play important performance-enhancing roles as animal feed additives, too. For decades, ingredients of humic substances have also been proven to carry potent antiviral effects against different viruses. Here, the antiviral activity of a humic substance containing ascorbic acid, Se- and Zn2+ ions intended as a nutritional supplement material was investigated against SARS-CoV-2 virus B1.1.7 Variant of Concern (Alpha Variant) in a VeroE6 cell line. Results show that this combination has a significant in vitro antiviral effect at a very low concentration range of its intended active ingredients. Even picomolar concentration ranges of humic substances, vitamin C and Zn/Se ions in the given composition were enough to achieve fifty percent viral replication inhibition in the applied SARS-CoV-2 virus inhibition test. Keywords: SARS-CoV-2, humic acid, fulvic acid, Zn-Se-ascorbic acid complex, antiviral activity, RT-PCR

scholarly journals In vitro Assessment of Antiviral Effect of Natural Compounds on Porcine Epidemic Diarrhea Coronavirus

2021 ◽  
Vol 8 ◽  
Author(s):  
Manuel Gómez-García ◽  
Héctor Puente ◽  
Héctor Argüello ◽  
Óscar Mencía-Ares ◽  
Pedro Rubio ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Formic Acid ◽  
Antiviral Agents ◽  
Antiviral Effect ◽  
Vero Cells ◽  
Optical Microscope ◽  
Dependent Manner ◽  
Diarrhea Virus ◽  
Porcine Epidemic Diarrhea

Organic acid and essential oils (EOs), well-known antimicrobials, could also possess antiviral activity, a characteristic which has not been completely addressed up to now. In this study, the effect of two organic acids (formic acid and sodium salt of coconut fatty acid distillates) and two single EO compounds (thymol and cinnamaldehye) was evaluated against porcine epidemic diarrhea virus (PEDV). The concentration used for each compound was established by cytotoxicity assays in Vero cells. The antiviral activity was then evaluated at three multiplicities of infection (MOIs) through visual cytopathic effect (CPE) evaluation and an alamarBlue assay as well as real-time reverse-transcription PCR (RT-qPCR) and viral titration of cell supernatants. Formic acid at at a dose of 1,200 ppm was the only compound which showed antiviral activity, with a weak reduction of CPE caused by PEDV. Through the alamarBlue fluorescence assay, we showed a significant anti-CPE effect of formic acid which could not be observed by using an inverted optical microscope. RT-qPCR and infectivity analysis also showed that formic acid significantly reduced viral RNA and viral titers in a PEDV MOI-dependent manner. Our results suggest that the antiviral activity of formic acid could be associated to its inhibitory effect on viral replication. Further studies are required to explore the anti-PEDV activity of formic acid under field conditions alone or together with other antiviral agents.

Effect of anaferon for children on the life cycle of influenza virus A/H1N1

2018 ◽  
pp. 87-94
Author(s):  
А.Г. Емельянова ◽  
М.В. Никифорова ◽  
Е.С. Дон ◽  
Н.Р. Махмудова ◽  
И.Н. Фалынскова ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Life Cycle ◽  
Antiviral Activity ◽  
Influenza A ◽  
Mdck Cells ◽  
Antiviral Effect ◽  
H1n1 Influenza ◽  
Dose Dependence ◽  
Influenza Virus A

Цель исследования - изучение возможного прямого влияния препарата «Анаферон детский» на жизненный цикл вируса гриппа А в процессе развития инфекции, а также дозозависимости противовирусного эффекта in vitro . Методика. Исследование противовирусной активности препарата «Анаферон детский» in vitro было проведено с использованием культуры клеток MDCK (Madin Darby canine kidney) и эталонных штаммов вируса гриппа A (H1N1) pdm09: A/California/07/09 и А/California/04/09, полученных от ВОЗ. Использовались методы оценки подавления Анафероном детским вирусной репликации (по результатам иммуноферментного анализа по определению экспрессии внутренних белков NP и M1 вируса гриппа А) и его влияние на ультраструктурные особенности морфогенеза вируса гриппа методом электронной микроскопии. В качестве положительного контроля был использован Озельтамивир карбоксилат в концентрации 10 мкМ. Для мониторинга валидности экспериментальной модели в работе использовали клетки, зараженные вирусом без добавления экспериментальных образцов (контроль вируса), а также интактные клетки (клеточный контроль). Результаты. В ходе исследования показан дозозависимый противовирусный эффект препарата «Анаферон детский» для 3 тестируемых разведений - 1/8, 1/12, 1/16. Методом электронной микроскопии показано, что применение препарата «Анаферон детский» при сравнении с контрольным образцом влияло на процесс почкования вирионов. Заключение. Впервые показана дозозависимость противовирусного действия препарата «Анаферон детский», а также подтверждена его эффективность в отношении двух штаммов вируса пандемического гриппа А/H1N1. Документировано, что применение препарата «Анаферон детский» нарушает жизненный цикл вируса гриппа А. Механизмы развития такого эффекта требуют дополнительного изучения, однако можно предположить их связь с ИФН-индуцирующими свойствами препарата «Анаферон детский», так как было показано, что в начале лечения вирусной инфекции препарат вызывает индукцию синтеза белков системы интерферонов. The aim of this study was to evaluate a possible direct effect of Anaferon for Children on the life cycle of influenza A virus during infection development and a dose response of the antiviral effect in vitro. Methods. The in vitro antiviral activity of Anaferon for Children was studied on cultured MDCK cells and reference strains of influenza virus A (H1N1) pdm09: A/California/07/09 and A/California/04/09, both from the WHO. Inhibition of viral replication by Anaferon for Children and its effect on ultrastructural features of the influenza morphogenesis were evaluated using electron microscopy. Results. The study demonstrated a dose dependence of Anaferon for Children antiviral activity for three dilutions - 1/8, 1/12, and 1/16. Anaferon for Children affected the process of virion budding as compared to placebo. Conclusion. The study showed that the anti-influenza action of Anaferon for Children was dose-dependent and confirmed that this drug was effective against two strains of pandemic A/H1N1 influenza. Furthermore, Anaferon for children disrupted one or several stages of the virus life cycle.

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