Nelfinavir markedly improves lung pathology in SARS-CoV-2-infected Syrian hamsters despite lack of an antiviral effect

Foo, Caroline Shi-Yan; Abdelnabi, Rana; Kaptein, Suzanne; Zhang, Xin; Horst, Sebastiaan ter; Mols, Raf; Rocha‐Pereira, Joana; Coelmont, Lotte; Leyssen, Pieter; Dallmeier, Kai; Vergote, Valentijn; Heylen, Elisabeth; Vangeel, Laura; Chatterjee, Arnab K.; Annaert, Pieter; Augustijns, Patrick; Jonghe, Steven De; Jochmans, Dirk; Weynand, Birgit; Neyts, Johan

doi:10.1101/2021.02.01.429108

Cited by 6 publications

(5 citation statements)

References 29 publications

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“…Concerning imatinib, as it did not work efficiently in HAE, nor in a hamster model despite a favorable pharmacokinetic profile, it seems that we are more in the Chloroquine configuration where in vitro activity does not translate to in vivo ( Tummino et al, 2021 ). Regarding an anti-inflammatory protective effect of imatinib on infected lungs, as observed for Nelfinavir ( Foo et al, 2021 ), more specific experiments are needed to decipher a potential beneficial effect since unreproducible improvements of the lung histopathological impairements were observed in this study. Moreover recent results of a randomised, placebo-controlled trial demonstrated that imatinib does not reduce the time to discontinuation of supplemental oxygen and mechanical ventilation in hospitalized COVID-19 patients ( Aman et al, 2021 ).…”

Section: Discussionmentioning

confidence: 86%

Preclinical evaluation of Imatinib does not support its use as an antiviral drug against SARS-CoV-2

et al. 2021

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Following the emergence of SARS-CoV-2, the search for an effective and rapidly available treatment was initiated worldwide based on repurposing of available drugs. Previous reports described the antiviral activity of certain tyrosine kinase inhibitors (TKIs) targeting the Abelson kinase 2 against pathogenic coronaviruses. Imatinib, one of them, has more than twenty years of safe utilization for the treatment of hematological malignancies. In this context, Imatinib was rapidly evaluated in clinical trials against Covid-19. Here, we present the pre-clinical evaluation of imatinib in multiple models. Our results indicated that imatinib and another TKI, the masitinib, exhibit an antiviral activity in VeroE6 cells. However, imatinib was inactive in a reconstructed bronchial human airway epithelium model. In vivo , imatinib therapy failed to impair SARS-CoV-2 replication in a golden Syrian hamster model despite high concentrations in plasma and in the lung. Overall, these results do not support the use of imatinib and similar TKIs as antivirals in the treatment of Covid-19.

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Section: Discussionmentioning

confidence: 86%

Preclinical evaluation of Imatinib does not support its use as an antiviral drug against SARS-CoV-2

et al. 2021

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“…Nelfinavir was also effective at dose-dependently inhibiting SARS-CoV-2 S protein—complete inhibition at the concentration of 10 μM—with no evidence of cellular cytotoxicity [ 141 ]. Remarkably, nelfinavir can also improve lung pathology caused by SARS-CoV-2 infection [ 142 ]. Nonetheless, nelfinavir might not benefit SARS-CoV-2-infected patients by reducing viral loads in the lungs, just as it does not reduce viral load in hamsters [ 142 ].…”

Section: Natural Products In Combination With the Fda-approved Drugs Inhibit Sars-cov-2mentioning

confidence: 99%

“…Remarkably, nelfinavir can also improve lung pathology caused by SARS-CoV-2 infection [ 142 ]. Nonetheless, nelfinavir might not benefit SARS-CoV-2-infected patients by reducing viral loads in the lungs, just as it does not reduce viral load in hamsters [ 142 ].…”

Section: Natural Products In Combination With the Fda-approved Drugs Inhibit Sars-cov-2mentioning

confidence: 99%

Natural Products, Alone or in Combination with FDA-Approved Drugs, to Treat COVID-19 and Lung Cancer

Yang

Wang

2021

Biomedicines

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As a public health emergency of international concern, the highly contagious coronavirus disease 2019 (COVID-19) pandemic has been identified as a severe threat to the lives of billions of individuals. Lung cancer, a malignant tumor with the highest mortality rate, has brought significant challenges to both human health and economic development. Natural products may play a pivotal role in treating lung diseases. We reviewed published studies relating to natural products, used alone or in combination with US Food and Drug Administration-approved drugs, active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and lung cancer from 1 January 2020 to 31 May 2021. A wide range of natural products can be considered promising anti-COVID-19 or anti-lung cancer agents have gained widespread attention, including natural products as monotherapy for the treatment of SARS-CoV-2 (ginkgolic acid, shiraiachrome A, resveratrol, and baicalein) or lung cancer (daurisoline, graveospene A, deguelin, and erianin) or in combination with FDA-approved anti-SARS-CoV-2 agents (cepharanthine plus nelfinavir, linoleic acid plus remdesivir) and anti-lung cancer agents (curcumin and cisplatin, celastrol and gefitinib). Natural products have demonstrated potential value and with the assistance of nanotechnology, combination drug therapies, and the codrug strategy, this “natural remedy” could serve as a starting point for further drug development in treating these lung diseases.

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“…Inhibits viral replication Strongly inhibited viral replication in Vero E6 cells [278] No activity found in vitro [279] Potential inhibitor against main protease (Mpro) [280] Did not reduce viral load in the lungs of SARS-CoV-2-infected hamsters, but markedly improved lung pathology despite a massive infiltration of neutrophils [281] Limited clinical data [288] No noticeable side effects [289] and larger clinical trials are needed…”

Section: Sars-cov-2mentioning

confidence: 99%

An Overview of Current Knowledge of Deadly CoVs and Their Interface with Innate Immunity

Zhang

Gargan

et al. 2021

Viruses

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Coronaviruses are a large family of zoonotic RNA viruses, whose infection can lead to mild or lethal respiratory tract disease. Severe Acute Respiratory Syndrome-Coronavirus-1 (SARS-CoV-1) first emerged in Guangdong, China in 2002 and spread to 29 countries, infecting 8089 individuals and causing 774 deaths. In 2012, Middle East Respiratory Syndrome-Coronavirus (MERS-CoV) emerged in Saudi Arabia and has spread to 27 countries, with a mortality rate of ~34%. In 2019, SARS-CoV-2 emerged and has spread to 220 countries, infecting over 100,000,000 people and causing more than 2,000,000 deaths to date. These three human coronaviruses cause diseases of varying severity. Most people develop mild, common cold-like symptoms, while some develop acute respiratory distress syndrome (ARDS). The success of all viruses, including coronaviruses, relies on their evolved abilities to evade and modulate the host anti-viral and pro-inflammatory immune responses. However, we still do not fully understand the transmission, phylogeny, epidemiology, and pathogenesis of MERS-CoV and SARS-CoV-1 and -2. Despite the rapid application of a range of therapies for SARS-CoV-2, such as convalescent plasma, remdesivir, hydroxychloroquine and type I interferon, no fully effective treatment has been determined. Remarkably, COVID-19 vaccine research and development have produced several offerings that are now been administered worldwide. Here, we summarise an up-to-date understanding of epidemiology, immunomodulation and ongoing anti-viral and immunosuppressive treatment strategies. Indeed, understanding the interplay between coronaviruses and the anti-viral immune response is crucial to identifying novel targets for therapeutic intervention, which may even prove invaluable for the control of future emerging coronavirus.

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Nelfinavir markedly improves lung pathology in SARS-CoV-2-infected Syrian hamsters despite lack of an antiviral effect

Cited by 6 publications

References 29 publications

Preclinical evaluation of Imatinib does not support its use as an antiviral drug against SARS-CoV-2

Preclinical evaluation of Imatinib does not support its use as an antiviral drug against SARS-CoV-2

Natural Products, Alone or in Combination with FDA-Approved Drugs, to Treat COVID-19 and Lung Cancer

An Overview of Current Knowledge of Deadly CoVs and Their Interface with Innate Immunity

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