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2.
Microbiol Spectr ; 10(1): e0150421, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1604818

ABSTRACT

In December 2019, a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started spreading worldwide causing the coronavirus disease 2019 (COVID-19) pandemic. The hyperactivation of the immune system has been proposed to account for disease severity and death in COVID-19 patients. Despite several approaches having been tested, no therapeutic protocol has been approved. Given that Cyclosporine A (CsA) is well-known to exert a strong antiviral activity on several viral strains and an anti-inflammatory role in different organs with relevant benefits in diverse pathological contexts, we tested its effects on SARS-CoV-2 infection of lung cells. We found that treatment with CsA either before or after infection of CaLu3 cells by three SARS-CoV-2 variants: (i) reduces the expression of both viral RNA and proteins in infected cells; (ii) decreases the number of progeny virions released by infected cells; (iii) dampens the virus-triggered synthesis of cytokines (including IL-6, IL-8, IL1α and TNF-α) that are involved in cytokine storm in patients. Altogether, these data provide a rationale for CsA repositioning for the treatment of severe COVID-19 patients. IMPORTANCE SARS-CoV-2 is the most recently identified member of the betacoronavirus genus responsible for the COVID-19 pandemic. Repurposing of available drugs has been a "quick and dirty" approach to try to reduce mortality and severe symptoms in affected patients initially, and can still represent an undeniable and valuable approach to face COVID-19 as the continuous appearance and rapid diffusion of more "aggressive"/transmissible variants, capable of eluding antibody neutralization, challenges the effectiveness of some anti-SARS-CoV-2 vaccines. Here, we tested a known antiviral and anti-inflammatory drug, Cyclosporine A (CsA), and found that it dampens viral infection and cytokine release from lung cells upon exposure to three different SARS-CoV-2 variants. Knock down of the main intracellular target of CsA, Cyclophilin A, does not phenocopy the drug inhibition of viral infection. Altogether, these findings shed new light on the cellular mechanisms of SARS-CoV-2 infection and provide the rationale for CsA repositioning to treat severe COVID-19 patients.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antiviral Agents/pharmacology , COVID-19/virology , Cyclosporine/pharmacology , Cytokines/immunology , Lung/virology , SARS-CoV-2/drug effects , Virus Release/drug effects , COVID-19/genetics , COVID-19/immunology , Cytokine Release Syndrome , Cytokines/genetics , Humans , SARS-CoV-2/genetics , SARS-CoV-2/physiology
3.
Cell Rep ; 35(1): 108959, 2021 04 06.
Article in English | MEDLINE | ID: covidwho-1163484

ABSTRACT

There is an urgent need for antivirals to treat the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To identify new candidates, we screen a repurposing library of ∼3,000 drugs. Screening in Vero cells finds few antivirals, while screening in human Huh7.5 cells validates 23 diverse antiviral drugs. Extending our studies to lung epithelial cells, we find that there are major differences in drug sensitivity and entry pathways used by SARS-CoV-2 in these cells. Entry in lung epithelial Calu-3 cells is pH independent and requires TMPRSS2, while entry in Vero and Huh7.5 cells requires low pH and triggering by acid-dependent endosomal proteases. Moreover, we find nine drugs are antiviral in respiratory cells, seven of which have been used in humans, and three are US Food and Drug Administration (FDA) approved, including cyclosporine. We find that the antiviral activity of cyclosporine is targeting Cyclophilin rather than calcineurin, revealing essential host targets that have the potential for rapid clinical implementation.


Subject(s)
COVID-19/drug therapy , Cyclosporine/pharmacology , Drug Repositioning , Epithelial Cells/metabolism , Lung/metabolism , SARS-CoV-2/metabolism , Animals , COVID-19/metabolism , COVID-19/pathology , Chlorocebus aethiops , Epithelial Cells/pathology , Epithelial Cells/virology , Humans , Lung/pathology , Lung/virology , Serine Endopeptidases/metabolism , United States , United States Food and Drug Administration , Vero Cells
4.
Drugs ; 81(5): 605-610, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1159706

ABSTRACT

Voclosporin (Lupkynis™) is an oral calcineurin inhibitor immunosuppressant that is being developed by Aurinia Pharmaceuticals. In January 2021, based on positive results from the pivotal phases II and III trials, oral voclosporin received its first approval in the USA for use in combination with a background immunosuppressive therapy regimen for adults with active lupus nephritis. Voclosporin is also being explored for the novel coronavirus disease 2019 (COVID-19) in kidney transplant recipients. This article summarizes the milestones in the development of voclosporin leading to this first approval for lupus nephritis.


Subject(s)
COVID-19/drug therapy , Calcineurin Inhibitors/therapeutic use , Cyclosporine/therapeutic use , Immunosuppressive Agents/therapeutic use , Kidney Transplantation , Animals , COVID-19/complications , Calcineurin Inhibitors/pharmacokinetics , Calcineurin Inhibitors/pharmacology , Cyclosporine/pharmacokinetics , Cyclosporine/pharmacology , Drug Approval , Humans , Immunosuppressive Agents/pharmacokinetics , Immunosuppressive Agents/pharmacology , Lupus Nephritis/drug therapy
6.
ACS Chem Neurosci ; 12(5): 930-944, 2021 03 03.
Article in English | MEDLINE | ID: covidwho-1091527

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV-2 represents a global public health emergency. The entry of SARS-CoV-2 into host cells requires the activation of its spike protein by host cell proteases. The serine protease, TMPRSS2, and cysteine proteases, Cathepsins B/L, activate spike protein and enable SARS-CoV-2 entry to the host cell through two completely different and independent pathways. Therefore, inhibiting either TMPRSS2 or cathepsin B/L may not sufficiently block the virus entry. We here hypothesized that simultaneous targeting of both the entry pathways would be more efficient to block the virus entry rather than targeting the entry pathways individually. To this end, we utilized the network-based drug repurposing analyses to identify the possible common drugs that can target both the entry pathways. This study, for the first time, reports the molecules like cyclosporine, calcitriol, and estradiol as candidate drugs with the binding ability to the host proteases, TMPRSS2, and cathepsin B/L. Next, we analyzed drug-gene and gene-gene interaction networks using 332 human targets of SARS-CoV-2 proteins. The network results indicate that, out of 332 human proteins, cyclosporine interacts with 216 (65%) proteins. Furthermore, we performed molecular docking and all-atom molecular dynamics (MD) simulations to explore the binding of drug with TMPRSS2 and cathepsin L. The molecular docking and MD simulation results showed strong and stable binding of cyclosporine A (CsA) with TMPRSS2 and CTSL genes. The above results indicate cyclosporine as a potential drug molecule, as apart from interacting with SARS-CoV-2 entry receptors, it also interacts with most of SARS-CoV-2 target host genes; thus it could potentially interfere with functions of SARS-CoV-2 proteins in human cells. We here also suggest that these antiviral drugs alone or in combination can simultaneously target both the entry pathways and thus can be considered as a potential treatment option for COVID-19.


Subject(s)
COVID-19/virology , Cyclosporine/pharmacology , Immunosuppressive Agents/pharmacology , SARS-CoV-2/drug effects , Virus Internalization/drug effects , Antiviral Agents/pharmacology , Cathepsin B/metabolism , Cathepsin L/metabolism , Drug Repositioning , Humans , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Serine Endopeptidases/metabolism
7.
Sheng Wu Gong Cheng Xue Bao ; 36(4): 605-611, 2020 Apr 25.
Article in Chinese | MEDLINE | ID: covidwho-1024807

ABSTRACT

Cyclophilin A (CypA) is a widely distributed and highly conserved protein in organisms. It has peptidyl-prolyl cis/trans isomerase activity and is a receptor for cyclosporin A (CsA). Coronaviruses are enveloped, single-stranded, positive-sense RNA viruses. Seven types of coronaviruses are currently known to infect humans, among which SARS-CoV, MERS-CoV, and SARS-CoV-2 are fatal for humans. It is well established that CypA is essential for the replication of various coronaviruses such as SARS-CoV, CoV-229E, CoV-NL63, and FCoV. Additionally, CsA and its derivatives (ALV, NIM811, etc.) have obvious inhibitory effects on a variety of coronaviruses. These results suggest that CypA is a potential antiviral target and the existing drug CsA might be used as an anti-coronavirus drug. At the end of 2019, SARS-CoV-2 raged in China, which seriously theatern human health and causes huge economic lases. In view of this, we describe the effects of CypA on the replication of coronaviruses and the antiviral activities of its inhibitors, which will provide the scientific basis and ideas for the development of antiviral drugs for SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus Infections , Coronavirus/drug effects , Coronavirus/growth & development , Cyclophilin A/antagonists & inhibitors , Cyclosporine/pharmacology , Cyclosporine/therapeutic use , Pandemics , Pneumonia, Viral , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/growth & development , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Cyclosporine/chemistry , Humans , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , SARS Virus/drug effects , SARS Virus/growth & development , SARS-CoV-2 , Virus Replication/drug effects
8.
Sci Rep ; 10(1): 22303, 2020 12 18.
Article in English | MEDLINE | ID: covidwho-989953

ABSTRACT

The increasing body of literature describing the role of host factors in COVID-19 pathogenesis demonstrates the need to combine diverse, multi-omic data to evaluate and substantiate the most robust evidence and inform development of therapies. Here we present a dynamic ranking of host genes implicated in human betacoronavirus infection (SARS-CoV-2, SARS-CoV, MERS-CoV, seasonal coronaviruses). We conducted an extensive systematic review of experiments identifying potential host factors. Gene lists from diverse sources were integrated using Meta-Analysis by Information Content (MAIC). This previously described algorithm uses data-driven gene list weightings to produce a comprehensive ranked list of implicated host genes. From 32 datasets, the top ranked gene was PPIA, encoding cyclophilin A, a druggable target using cyclosporine. Other highly-ranked genes included proposed prognostic factors (CXCL10, CD4, CD3E) and investigational therapeutic targets (IL1A) for COVID-19. Gene rankings also inform the interpretation of COVID-19 GWAS results, implicating FYCO1 over other nearby genes in a disease-associated locus on chromosome 3. Researchers can search and review the gene rankings and the contribution of different experimental methods to gene rank at https://baillielab.net/maic/covid19 . As new data are published we will regularly update the list of genes as a resource to inform and prioritise future studies.


Subject(s)
COVID-19/epidemiology , COVID-19/genetics , Algorithms , CD3 Complex/genetics , CD4 Antigens/genetics , Chemokine CXCL10/genetics , Computational Biology , Cyclophilin A/genetics , Cyclosporine/pharmacology , Databases, Genetic , Genome-Wide Association Study , Genomics , Humans , Immune System , Immunogenetics , Inflammation , Interleukin-1alpha/genetics , Microtubule-Associated Proteins/genetics , Proteomics
9.
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
10.
Antiviral Res ; 181: 104878, 2020 09.
Article in English | MEDLINE | ID: covidwho-645295

ABSTRACT

In response to the current pandemic caused by the novel SARS-CoV-2, identifying and validating effective therapeutic strategies is more than ever necessary. We evaluated the in vitro antiviral activities of a shortlist of compounds, known for their cellular broad-spectrum activities, together with drugs that are currently under evaluation in clinical trials for COVID-19 patients. We report the antiviral effect of remdesivir, lopinavir, chloroquine, umifenovir, berberine and cyclosporine A in Vero E6 cells model of SARS-CoV-2 infection, with estimated 50% inhibitory concentrations of 0.99, 5.2, 1.38, 3.5, 10.6 and 3 µM, respectively. Virus-directed plus host-directed drug combinations were also investigated. We report a strong antagonism between remdesivir and berberine, in contrast with remdesivir/diltiazem, for which we describe high levels of synergy, with mean Loewe synergy scores of 12 and peak values above 50. Combination of host-directed drugs with direct acting antivirals underscore further validation in more physiological models, yet they open up interesting avenues for the treatment of COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drug Repositioning , Pandemics , Pneumonia, Viral/drug therapy , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , Berberine/pharmacology , COVID-19 , Chlorocebus aethiops , Chloroquine/pharmacology , Coronavirus Infections/virology , Cyclosporine/pharmacology , Drug Antagonism , Drug Combinations , Drug Synergism , Humans , Indoles/pharmacology , Lopinavir/pharmacology , Pneumonia, Viral/virology , SARS-CoV-2 , Vero Cells
11.
Transpl Infect Dis ; 22(6): e13404, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-635705

ABSTRACT

Severe acute respiratory syndrome Coronavirus 2 (SARS-Cov2) outbreak has caused a pandemic rapidly impacting on the way of life of the entire world. This impact in the specific setting of transplantation and immunosuppression has been poorly explored to date. Discordant data exist on the impact of previous coronavirus outbreaks on immunosuppressed patients. Overall, only a very limited number of cases have been reported in literature, suggesting that transplanted patients not necessarily present an increased risk of severe SARS-Cov2-related disease compared to the general population. We conducted a literature review related to the impact of immunosuppression on coronavirus infections including case reports and series describing immunosuppression management in transplant recipients. The role of steroids, calcineurin inhibitors, and mycophenolic acid has been explored more in detail. A point-in-time snapshot of the yet released literature and some considerations in relation to the use of immunosuppression in SARS-Cov2 infected transplant recipients are provided here for the physicians dealing with immunocompromised patients.


Subject(s)
COVID-19/immunology , Immunocompromised Host , Transplant Recipients , COVID-19/complications , COVID-19/epidemiology , Calcineurin Inhibitors/pharmacology , Cyclosporine/pharmacology , Female , Humans , Kidney Transplantation , Male , Pandemics , SARS-CoV-2 , Steroids/administration & dosage , Tacrolimus/pharmacology
12.
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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