Combined in silico and in vitro approaches identified the antipsychotic drug lurasidone and the antiviral drug elbasvir as SARS-CoV2 and HCoV-OC43 inhibitors

Milani, Mario; Donalisio, Manuela; Bonotto, Rafaela Milan; Schneider, Edoardo; Arduino, Irene; Bonì, Francesco; Lembo, David; Marcello, Alessandro; Mastrangelo, Eloise

doi:10.1016/j.antiviral.2021.105055

Cited by 31 publications

(31 citation statements)

References 63 publications

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“…To highlight the role of inhibitors of glycosylases in the context of SARS-CoV-2 infection, both Miglustat and the Castanospermine pro-drug Celgosivir were tested in parallel in a high-throughput assay based on Huh7-hACE2 cells recently developed [ 30 ]. As shown in Figure 3 a, Miglustat confirmed its antiviral potential with an EC 50 of 19.9 ± 3.4 μM.…”

Section: Resultsmentioning

confidence: 99%

“…The assay is described in detail elsewhere [ 30 ]; briefly, Huh 7-hACE2 cells were seeded overnight to adhere to a 96-well plate, treated with serial dilution of the compounds, and then infected with SARS-CoV-2 with appropriate controls (vehicle, not infected, infected and not treated, and infected and treated with the control inhibitor hydroxychloroquine). The plates were incubated for 20 h at 37 °C, and then fixed with 4% PFA, permeabilized with 0.1% of Triton-X for 15 min and incubated in blocking buffer (PBS containing 1% of BSA).…”

Section: Methodsmentioning

confidence: 99%

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Inhibitors of Protein Glycosylation Are Active against the Coronavirus Severe Acute Respiratory Syndrome Coronavirus SARS-CoV-2

Rajasekharan

Bonotto

Alves

et al. 2021

Viruses

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Repurposing clinically available drugs to treat the new coronavirus disease 2019 (COVID-19) is an urgent need in the course of the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-2) pandemic, as very few treatment options are available. The iminosugar Miglustat is a well-characterized drug for the treatment of rare genetic lysosome storage diseases, such as Gaucher and Niemann-Pick type C, and has also been described to be active against a variety of enveloped viruses. The activity of Miglustat is here demonstrated in the micromolar range for SARS-CoV-2 in vitro. The drug acts at the post-entry level and leads to a marked decrease of viral proteins and release of infectious viruses. The mechanism resides in the inhibitory activity toward α-glucosidases that are involved in the early stages of glycoprotein N-linked oligosaccharide processing in the endoplasmic reticulum, leading to a marked decrease of the viral Spike protein. Indeed, the antiviral potential of protein glycosylation inhibitors against SARS-CoV-2 is further highlighted by the low-micromolar activity of the investigational drug Celgosivir. These data point to a relevant role of this approach for the treatment of COVID-19.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Inhibitors of Protein Glycosylation Are Active against the Coronavirus Severe Acute Respiratory Syndrome Coronavirus SARS-CoV-2

Rajasekharan

Bonotto

Alves

et al. 2021

Viruses

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“…Similar to chlorpromazine, several older antipsychotics have in vitro activity against SARS-CoV-2 but offer no advantage while the second-generation antipsychotics (SGA) are generally much less active with the possible exception of lurasidone 18 . Nevertheless, clinical data is still missing.…”

Section: Chlorpromazine and Other Antipsychoticsmentioning

confidence: 99%

Neuropsychiatric Drugs Against COVID-19: What is the Clinical Evidence?

2022

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Since the beginning of the coronavirus disease (COVID)-19 pandemic, the need for effective treatments for COVID-19 led to the idea of “repurposing” drugs for antiviral treatment. Several antipsychotics and antidepressants have been tested for in vitro activity against the severe acute respiratory syndrome coronavirus 2. Chlorpromazine, other phenothiazine antipsychotics, and the antidepressant fluoxetine were found to be rather potent in these studies. However, whether effective plasma concentrations can be obtained with clinically accepted doses of these drugs is not clear. Data of COVID-19 patients are not yet available but several clinical studies are currently underway.The specific serotonin reuptake inhibitor fluvoxamine is a potent Sigma-1 receptor agonist and reduces inflammation in animal models of cytokine-stress. Accordingly, fluvoxamine treatment was superior to placebo in reducing impaired respiratory function and other symptoms of inflammation in COVID-19 patients in a placebo-controlled clinical study and another open clinical trial. The beneficial effects of fluvoxamine on the course of COVID-19 were recently confirmed in a large placebo-controlled double-blind trial with several hundred patients.Inflammation represents a major risk factor for many psychiatric disorders which explains the high susceptibilitiy of COVID-19 patients for psychiatric diseases. Many antidepressants and antipsychotics possess anti-inflammatory properties independent of sigma-1 activity which might be important to reduce psychiatric symptoms of COVID-19 patients and to improve respiratory dysfunction and other consequences of inflammation. This might explain the rather unspecific benefit which has been reported for several cohorts of COVID-19 patients treated with different psychotropic drugs.

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“…For flow cytometer analysis, HEK-293T cells expressing ACE2 receptor were incubated 1h at 4 °C in the presence of purified RBD, the primary mouse antibody CR3022-AbSIP and the secondary anti Human IgG goat antibody Alexa 488 [ 29 ]. 96-well ELISA Maxi Sorp Immuno-Plates (Thermofisher) were coated with SARS-CoV-2 RBD (1 μg/mL in PBS pH 7.4) and incubated overnight at 4 °C.…”

Section: Methodsmentioning

confidence: 99%

Expression, purification and characterization of SARS-CoV-2 spike RBD in ExpiCHO cells

March

Terdoslavich

Polez

et al. 2022

Protein Expression and Purification

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Reliable diagnosis is critical to identify infections of SARS-CoV-2 as well as to evaluate the immune response to virus and vaccines. Consequently, it becomes crucial the isolation of sensitive antibodies to use as immunocapture elements of diagnostic tools. The final bottleneck to achieve these results is the availability of enough antigen of good quality. We have established a robust pipeline for the production of recombinant, functional SARS-CoV-2 Spike receptor binding domain (RBD) at high yield and low cost in culture flasks. RBD was expressed in transiently transfected ExpiCHO cells at 32 °C and 5% CO 2 and purified up to 40 mg/L. The progressive protein accumulation in the culture medium was monitored with an immunobinding assay in order to identify the optimal collection time. Successively, a two-step chromatographic protocol enabled its selective purification in the monomeric state. RBD quality assessment was positively evaluated by SDS-PAGE, Western Blotting and Mass Spectrometry, while Bio-Layer Interferometry, flow cytometer and ELISA tests confirmed its functionality. This effective protocol for the RBD production in transient eukaryotic system can be immediately extended to the production of RBD mutants.

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Combined in silico and in vitro approaches identified the antipsychotic drug lurasidone and the antiviral drug elbasvir as SARS-CoV2 and HCoV-OC43 inhibitors

Cited by 31 publications

References 63 publications

Inhibitors of Protein Glycosylation Are Active against the Coronavirus Severe Acute Respiratory Syndrome Coronavirus SARS-CoV-2

Inhibitors of Protein Glycosylation Are Active against the Coronavirus Severe Acute Respiratory Syndrome Coronavirus SARS-CoV-2

Neuropsychiatric Drugs Against COVID-19: What is the Clinical Evidence?

Expression, purification and characterization of SARS-CoV-2 spike RBD in ExpiCHO cells

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