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1.
Clin Infect Dis ; 71(16): 2191-2194, 2020 11 19.
Article in English | MEDLINE | ID: covidwho-1153166

ABSTRACT

December 2019 saw the emergence of a new epidemic of pneumonia of varying severity, called coronavirus disease 2019 (COVID-19), caused by a newly identified coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV-2). No therapeutic option is available to treat this infection that has already killed > 310 000 people worldwide. This Viewpoint summarizes the strong scientific arguments supporting the use of alisporivir, a nonimmunosuppressive analogue of cyclosporine A with potent cyclophilin inhibition properties that has reached phase 3 clinical development, for the treatment of COVID-19. They include the strong cyclophilin dependency of the life cycle of many coronaviruses, including severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus, and preclinical data showing strong antiviral and cytoprotective properties of alisporivir in various models of coronavirus infection, including SARS-CoV-2. Alisporivir should be tested without delay on both virological and clinical endpoints in patients with or at risk of severe forms of SARS-CoV-2 infection.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Cyclophilins/antagonists & inhibitors , Cyclosporine/therapeutic use , SARS-CoV-2/drug effects , Animals , COVID-19/epidemiology , Clinical Trials as Topic , Disease Models, Animal , Humans , Mice , Rats
2.
Eur Respir J ; 56(5)2020 Nov.
Article in English | MEDLINE | ID: covidwho-648811

ABSTRACT

While severe coronavirus infections, including Middle East respiratory syndrome coronavirus (MERS-CoV), cause lung injury with high mortality rates, protective treatment strategies are not approved for clinical use.We elucidated the molecular mechanisms by which the cyclophilin inhibitors cyclosporin A (CsA) and alisporivir (ALV) restrict MERS-CoV to validate their suitability as readily available therapy in MERS-CoV infection.Calu-3 cells and primary human alveolar epithelial cells (hAECs) were infected with MERS-CoV and treated with CsA or ALV or inhibitors targeting cyclophilin inhibitor-regulated molecules including calcineurin, nuclear factor of activated T-cells (NFATs) or mitogen-activated protein kinases. Novel CsA-induced pathways were identified by RNA sequencing and manipulated by gene knockdown or neutralising antibodies. Viral replication was quantified by quantitative real-time PCR and 50% tissue culture infective dose. Data were validated in a murine MERS-CoV infection model.Both CsA and ALV reduced MERS-CoV titres and viral RNA replication in Calu-3 cells and hAECs, improving epithelial integrity. While neither calcineurin nor NFAT inhibition reduced MERS-CoV propagation, blockade of c-Jun N-terminal kinase diminished infectious viral particle release but not RNA accumulation. Importantly, CsA induced interferon regulatory factor 1 (IRF1), a pronounced type III interferon (IFNλ) response and expression of antiviral genes. Downregulation of IRF1 or IFNλ increased MERS-CoV propagation in the presence of CsA. Importantly, oral application of CsA reduced MERS-CoV replication in vivo, correlating with elevated lung IFNλ levels and improved outcome.We provide evidence that cyclophilin inhibitors efficiently decrease MERS-CoV replication in vitro and in vivo via upregulation of inflammatory antiviral cell responses, in particular IFNλ. CsA might therefore represent a promising candidate for treating MERS-CoV infection.


Subject(s)
Coronavirus Infections/prevention & control , Cyclophilins/antagonists & inhibitors , Cyclosporine/pharmacology , Interferons/metabolism , Middle East Respiratory Syndrome Coronavirus/drug effects , Alveolar Epithelial Cells/drug effects , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/virology , Animals , Calcineurin Inhibitors/pharmacology , Cell Culture Techniques , Coronavirus Infections/metabolism , Disease Models, Animal , Humans , Interferon Regulatory Factor-1/drug effects , Interferon Regulatory Factor-1/metabolism , Interferons/drug effects , Mice , Middle East Respiratory Syndrome Coronavirus/physiology , Virus Replication/drug effects
3.
Antimicrob Agents Chemother ; 64(7)2020 06 23.
Article in English | MEDLINE | ID: covidwho-197789

ABSTRACT

Cyclophilins play a key role in the life cycle of coronaviruses. Alisporivir (Debio 025) is a nonimmunosuppressive analogue of cyclosporine with potent cyclophilin inhibition properties. Alisporivir reduced SARS-CoV-2 RNA production in a dose-dependent manner in Vero E6 cells, with a 50% effective concentration (EC50) of 0.46 ± 0.04 µM. Alisporivir inhibited a postentry step of the SARS-CoV-2 life cycle. These results justify rapidly conducting a proof-of-concept phase 2 trial with alisporivir in patients with SARS-CoV-2 infection.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Cyclophilins/antagonists & inhibitors , Cyclosporine/pharmacology , Pneumonia, Viral/drug therapy , Animals , Antiviral Agents/pharmacology , COVID-19 , Cell Line , Chlorocebus aethiops , Humans , Pandemics , SARS-CoV-2 , Vero Cells , Virus Replication/drug effects
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