Celastrol: A lead compound that inhibits SARS‐CoV‐2 replication, the activity of viral and human cysteine proteases, and virus‐induced IL‐6 secretion

Fuzo, Carlos Alessandro; Martins, Ronaldo Teixeira; Fraga-Silva, Thais Fernanda de Campos; Amstalden, Martin K.; Leo, Thais Canassa De; Souza, Juliano P.; Lima, Thais M.; Faccioli, Lúcia Helena; Okamoto, Débora N.; Juliano, María A.; França, Suzelei de Castro; Juliano, Luiz; Bonato, Vânia L D; Arruda, Eurico; Dias‐Baruffi, Marcelo

doi:10.1002/ddr.21982

Cited by 10 publications

(3 citation statements)

References 134 publications

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“…46 Compared to M pro , there have been far fewer publications describing studies attempting to find PL pro inhibitors. For example, one study identified disulfiram and analogues 47 as covalent inhibitors and another described the natural product celastrol, 48 which binds similarly to PL pro , M pro , and cathepsin L. Yet, another natural product, anarcardic acid, is a weak inhibitor of PL pro and M pro . 49 An initial hit for PL pro came from the naphthalene derivative GRL-0617, which had previously been identified for SARS-CoV and demonstrated activity against SARS-CoV-2.…”

Section: ■ Discussionmentioning

confidence: 99%

Discovery of PL^pro and M^pro Inhibitors for SARS-CoV-2

et al. 2023

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There are very few small-molecule antivirals for SARS-CoV-2 that are either currently approved (or emergency authorized) in the US or globally, including remdesivir, molnupiravir, and paxlovid. The increasing number of SARS-CoV-2 variants that have appeared since the outbreak began over three years ago raises the need for continual development of updated vaccines and orally available antivirals in order to fully protect or treat the population. The viral main protease (Mpro) and the papain-like protease (PLpro) are key for viral replication; therefore, they represent valuable targets for antiviral therapy. We herein describe an in vitro screen performed using the 2560 compounds from the Microsource Spectrum library against Mpro and PLpro in an attempt to identify additional small-molecule hits that could be repurposed for SARS-CoV-2. We subsequently identified 2 hits for Mpro and 8 hits for PLpro. One of these hits was the quaternary ammonium compound cetylpyridinium chloride with dual activity (IC50 = 2.72 ± 0.09 μM for PLpro and IC50 = 7.25 ± 0.15 μM for Mpro). A second inhibitor of PLpro was the selective estrogen receptor modulator raloxifene (IC50 = 3.28 ± 0.29 μM for PLpro and IC50 = 42.8 ± 6.7 μM for Mpro). We additionally tested several kinase inhibitors and identified olmutinib (IC50 = 0.54 ± 0.04 μM), bosutinib (IC50 = 4.23 ± 0.28 μM), crizotinib (IC50 = 3.81 ± 0.04 μM), and dacominitinib (IC50 = IC50 3.33 ± 0.06 μM) as PLpro inhibitors for the first time. In some cases, these molecules have also been tested by others for antiviral activity for this virus, or we have used Calu-3 cells infected with SARS-CoV-2. The results suggest that approved drugs can be identified with promising activity against these proteases, and in several cases we or others have validated their antiviral activity. The additional identification of known kinase inhibitors as molecules targeting PLpro may provide new repurposing opportunities or starting points for chemical optimization.

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Section: ■ Discussionmentioning

confidence: 99%

Discovery of PL^pro and M^pro Inhibitors for SARS-CoV-2

et al. 2023

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“…In vitro [271][272][273][274] AD: Alzheimer's disease; PD: Parkinson's disease; HMGB1: high mobility group box 1 protein.…”

Section: Prevents Oxidative Stressmentioning

confidence: 99%

Neuroprotective Agents with Therapeutic Potential for COVID-19

Zaa,

Espitia,

Reyes-Barrera

et al. 2023

Biomolecules

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COVID-19 patients can exhibit a wide range of clinical manifestations affecting various organs and systems. Neurological symptoms have been reported in COVID-19 patients, both during the acute phase of the illness and in cases of long-term COVID. Moderate symptoms include ageusia, anosmia, altered mental status, and cognitive impairment, and in more severe cases can manifest as ischemic cerebrovascular disease and encephalitis. In this narrative review, we delve into the reported neurological symptoms associated with COVID-19, as well as the underlying mechanisms contributing to them. These mechanisms include direct damage to neurons, inflammation, oxidative stress, and protein misfolding. We further investigate the potential of small molecules from natural products to offer neuroprotection in models of neurodegenerative diseases. Through our analysis, we discovered that flavonoids, alkaloids, terpenoids, and other natural compounds exhibit neuroprotective effects by modulating signaling pathways known to be impacted by COVID-19. Some of these compounds also directly target SARS-CoV-2 viral replication. Therefore, molecules of natural origin show promise as potential agents to prevent or mitigate nervous system damage in COVID-19 patients. Further research and the evaluation of different stages of the disease are warranted to explore their potential benefits.

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“…More importantly, a previous in vitro study reported that TP could bind to the main protease (M pro ) and receptor-binding domain (RBD) of SARS-CoV-2 and is able to reverse gene expression signature and inhibit the virus replication in SARS-CoV-2-infected cells. 21 Echoing these findings, we managed to assess the therapeutic value of TP lipo for the treatment of COVID-19.…”

Section: Introductionmentioning

confidence: 99%

Tripterin liposome relieves severe acute respiratory syndrome as a potent COVID-19 treatment

Que

Hong

Lan

et al. 2022

Sig Transduct Target Ther

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For coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 15–30% of patients are likely to develop COVID-19-related acute respiratory distress syndrome (ARDS). There are still few effective and well-understood therapies available. Novel variants and short-lasting immunity are posing challenges to vaccine efficacy, so finding antiviral and antiinflammatory treatments remains crucial. Here, tripterin (TP), a traditional Chinese medicine, was encapsulated into liposome (TP lipo) to investigate its antiviral and antiinflammatory effects in severe COVID-19. By using two severe COVID-19 models in human ACE2-transgenic (hACE2) mice, an analysis of TP lipo’s effects on pulmonary immune responses was conducted. Pulmonary pathological alterations and viral burden were reduced by TP lipo treatment. TP lipo inhibits SARS-CoV-2 replication and hyperinflammation in infected cells and mice, two crucial events in severe COVID-19 pathophysiology, it is a promising drug candidate to treat SARS-CoV-2-induced ARDS.

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Celastrol: A lead compound that inhibits SARS‐CoV‐2 replication, the activity of viral and human cysteine proteases, and virus‐induced IL‐6 secretion

Cited by 10 publications

References 134 publications

Discovery of PL^pro and M^pro Inhibitors for SARS-CoV-2

Discovery of PL^pro and M^pro Inhibitors for SARS-CoV-2

Neuroprotective Agents with Therapeutic Potential for COVID-19

Tripterin liposome relieves severe acute respiratory syndrome as a potent COVID-19 treatment

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Celastrol: A lead compound that inhibits SARS‐CoV‐2 replication, the activity of viral and human cysteine proteases, and virus‐induced IL‐6 secretion

Cited by 10 publications

References 134 publications

Discovery of PLpro and Mpro Inhibitors for SARS-CoV-2

Discovery of PLpro and Mpro Inhibitors for SARS-CoV-2

Neuroprotective Agents with Therapeutic Potential for COVID-19

Tripterin liposome relieves severe acute respiratory syndrome as a potent COVID-19 treatment

Contact Info

Product

Resources

About

Discovery of PL^pro and M^pro Inhibitors for SARS-CoV-2

Discovery of PL^pro and M^pro Inhibitors for SARS-CoV-2