Browse
Submit Data
Databases
API
Help

Dataset Information

12 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Caspases and therapeutic potential of caspase inhibitors in moderate-severe SARS-CoV-2 infection and long COVID.

ABSTRACT:

Background

COVID-19 can present with lymphopenia and extraordinary complex multiorgan pathologies that can trigger long-term sequela.

Aims

Given that inflammasome products, like caspase-1, play a role in the pathophysiology of a number of co-morbid conditions, we investigated caspases across the spectrum of COVID-19 disease.

Materials & methods

We assessed transcriptional states of multiple caspases and using flow cytometry, the expression of active caspase-1 in blood cells from COVID-19 patients in acute and convalescent stages of disease. Non-COVID-19 subject presenting with various comorbid conditions served as controls.

Results

Single-cell RNA-seq data of immune cells from COVID-19 patients showed a distinct caspase expression pattern in T cells, neutrophils, dendritic cells, and eosinophils compared with controls. Caspase-1 was upregulated in CD4+ T-cells from hospitalized COVID-19 patients compared with unexposed controls. Post-COVID-19 patients with lingering symptoms (long-haulers) also showed upregulated caspase-1activity in CD4+ T-cells that ex vivo was attenuated with a select pan-caspase inhibitor. We observed elevated caspase-3/7levels in red blood cells from COVID-19 patients compared with controls that was reduced following caspase inhibition.

Discussion

Our preliminary results suggest an exuberant caspase response in COVID-19 that may facilitate immune-related pathological processes leading to severe outcomes. Further clinical correlations of caspase expression in different stages of COVID-19 will be needed.

Conclusion

Pan-caspase inhibition could emerge as a therapeutic strategy to ameliorate or prevent severe COVID-19.

SUBMITTER: Plassmeyer M

PROVIDER: S-EPMC8222863 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Chinese Therapeutic Strategy for Fighting COVID-19 and Potential Small-Molecule Inhibitors against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).

Project description:The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to more than 20 million people infected worldwide with an average mortality rate of 3.6%. This virus poses major challenges to public health, as it not only is highly contagious but also can be transmitted by asymptomatic infected individuals. COVID-19 is clinically difficult to manage due to a lack of specific antiviral drugs or vaccines. In this article, Chinese therapy strategies for treating COVID-19 patients, including current applications of traditional Chinese medicine (TCM), are comprehensively reviewed. Furthermore, 72 small molecules from natural products and TCM with reported antiviral activity against human coronaviruses (CoVs) are identified from published literature, and their potential applications in combating SARS-CoV-2 are discussed. Among these, the clinical efficacies of some accessible drugs such as remdesivir (RDV) and favipiravir (FPV) for COVID-19 are emphatically summarized. We hope this review provides a foundation for managing the worsening pandemic and developing antivirals against SARS-CoV-2.

| S-EPMC7489051 | biostudies-literature

Therapeutic potential of long-acting opioids and opioid antagonists for SARS-CoV-2 infection.

Project description: Not available

| S-EPMC8418909 | biostudies-literature

Potential SARS-CoV-2 main protease inhibitors.

Project description:The coronavirus disease 2019 (COVID-19) pandemic has prompted an urgent need for new treatment strategies. No target-specific drugs are currently available for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but new drug candidates targeting the viral replication cycle are being explored. A prime target of drug-discovery efforts is the SARS-CoV-2 main protease (Mpro). The main proteases of different coronaviruses, including SARS-CoV-2, SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), share a structurally conserved substrate-binding region that can be exploited to design new protease inhibitors. With the recent reporting of the X-ray crystal structure of the SARS-CoV-2 Mpro, studies to discover Mpro inhibitors using both virtual and in vitro screening are progressing rapidly. This review focusses on the recent developments in the search for small-molecule inhibitors targeting the SARS-CoV-2 Mpro.

| S-EPMC7724992 | biostudies-literature

Potential therapeutic use of corticosteroids as SARS CoV-2 main protease inhibitors: a computational study.

Project description:The outbreak of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), represents a pandemic threat to global public health. To date, ?530,000 people died of this disease worldwide. Presently, researchers/clinicians are adopting the drug repurposing strategy to combat this disease. It has also been observed that some repurposed anti-viral drugs may serve as potent inhibitors of SARS CoV-2 Mpro, a key component of viral replication. Apart from these anti-viral drugs, recently dexamethasone (an important corticosteroid) is effectively used to treat COVID-19 patients. However, the mechanism behind the mode of its action is not so clear. Additionally, the effect of other well-known corticosteroids to control this disease by inhibiting the proteolytic activity of Mpro is ambiguous. In this study, we have adopted computational approaches to understand these aspects. Six well-known corticosteroids (cortisone, hydrocortisone, prednisolone, methylprednisolone, betamethasone and dexamethasone) and two repurposed drugs (darunavir and lopinavir) against COVID-19 were subjected for molecular docking studies. Two of them (betamethasone and dexamethasone) were selected by comparing their binding affinities with selected repurposed drugs toward Mpro. Betamethasone and dexamethasone interacted with both the catalytic residues of Mpro (His41 and Cys145). Molecular dynamics studies further revealed that these two Mpro-corticosteroid complexes are more stable, experience less conformational fluctuations and more compact than Mpro-darunavir/lopinavir complexes. These findings were additionally validated by MM-GBSA analysis. This study provides corroboration for execution of anti-COVID-19 activity of dexamethasone. Our study also emphasizes on the use of another important corticosteroid (betamethasone) as potential therapeutic agent for COVID-19 treatment.

| S-EPMC7596904 | biostudies-literature

Caspases in metabolic disease and their therapeutic potential.

Project description:Caspases, a family of cysteine-dependent aspartate-specific proteases, are central to the maintenance of cellular and organismal homoeostasis by functioning as key mediators of the inflammatory response and/or apoptosis. Both metabolic inflammation and apoptosis play a central role in the pathogenesis of metabolic disease such as obesity and the progression of nonalcoholic steatohepatisis (NASH) to more severe liver disease. Obesity and nonalcoholic fatty liver disease (NAFLD) are the leading global health challenges associated with the development of numerous comorbidities including insulin resistance, type-2 diabetes and early mortality. Despite the high prevalence, current treatment strategies including lifestyle, dietary, pharmaceutical and surgical interventions, are often limited in their efficacy to manage or treat obesity, and there are currently no clinical therapies for NAFLD/NASH. As mediators of inflammation and cell death, caspases are attractive therapeutic targets for the treatment of these metabolic diseases. As such, pan-caspase inhibitors that act by blocking apoptosis have reached phase I/II clinical trials in severe liver disease. However, there is still a lack of knowledge of the specific and differential functions of individual caspases. In addition, cross-talk between alternate cell death pathways is a growing concern for long-term caspase inhibition. Evidence is emerging of the important cell-death-independent, non-apoptotic functions of caspases in metabolic homoeostasis that may be of therapeutic value. Here, we review the current evidence for roles of caspases in metabolic disease and discuss their potential targeting as a therapeutic strategy.

| S-EPMC5988802 | biostudies-literature

Computational Design of Miniproteins as SARS-CoV-2 Therapeutic Inhibitors.

Project description:A rational therapeutic strategy is urgently needed for combating SARS-CoV-2 infection. Viral infection initiates when the SARS-CoV-2 receptor-binding domain (RBD) binds to the ACE2 receptor, and thus, inhibiting RBD is a promising therapeutic for blocking viral entry. In this study, the structure of lead antiviral candidate binder (LCB1), which has three alpha-helices (H1, H2, and H3), is used as a template to design and simulate several miniprotein RBD inhibitors. LCB1 undergoes two modifications: structural modification by truncation of the H3 to reduce its size, followed by single and double amino acid substitutions to enhance its binding with RBD. We use molecular dynamics (MD) simulations supported by ab initio density functional theory (DFT) calculations. Complete binding profiles of all miniproteins with RBD have been determined. The MD investigations reveal that the H3 truncation results in a small inhibitor with a -1.5 kcal/mol tighter binding to RBD than original LCB1, while the best miniprotein with higher binding affinity involves D17R or E11V + D17R mutation. DFT calculations provide atomic-scale details on the role of hydrogen bonding and partial charge distribution in stabilizing the minibinder:RBD complex. This study provides insights into general principles for designing potential therapeutics for SARS-CoV-2.

| S-EPMC8776159 | biostudies-literature

Potential inhibitors for the novel coronavirus (SARS-CoV-2).

Project description:The lack of a vaccine or any effective treatment for the aggressive novel coronavirus disease (COVID-19) has created a sense of urgency for the discovery of effective drugs. Several repurposing pharmaceutical candidates have been reported or envisaged to inhibit the emerging infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but their binding sites, binding affinities and inhibitory mechanisms are still unavailable. In this study, we use the ligand-protein docking program and molecular dynamic simulation to ab initio investigate the binding mechanism and inhibitory ability of seven clinically approved drugs (Chloroquine, Hydroxychloroquine, Remdesivir, Ritonavir, Beclabuvir, Indinavir and Favipiravir) and a recently designed ?-ketoamide inhibitor (13b) at the molecular level. The results suggest that Chloroquine has the strongest binding affinity with 3CL hydrolase (Mpro) among clinically approved drugs, indicating its effective inhibitory ability for SARS-CoV-2. However, the newly designed inhibitor 13b shows potentially improved inhibition efficiency with larger binding energy compared with Chloroquine. We further calculate the important binding site residues at the active site and demonstrate that the MET 165 and HIE 163 contribute the most for 13b, while the MET 165 and GLN 189 for Chloroquine, based on residual energy decomposition analysis. The proposed work offers a higher research priority for 13b to treat the infection of SARS-CoV-2 and provides theoretical basis for further design of effective drug molecules with stronger inhibition.

| S-EPMC7543260 | biostudies-literature

Identification of proteasome and caspase inhibitors targeting SARS-CoV-2 M<sup>pro</sup>.

Project description: Not available

| S-EPMC8166895 | biostudies-literature

SARS-CoV-2 Infection and Lung Cancer: Potential Therapeutic Modalities.

Project description:Human coronaviruses, especially SARS-CoV-2, are emerging pandemic infectious diseases with high morbidity and mortality in certain group of patients. In general, SARS-CoV-2 causes symptoms ranging from the common cold to severe conditions accompanied by lung injury, acute respiratory distress syndrome in addition to other organs' destruction. The main impact upon SARS-CoV-2 infection is damage to alveolar and acute respiratory failure. Thus, lung cancer patients are identified as a particularly high-risk group for SARS-CoV-2 infection and its complications. On the other hand, it has been reported that SARS-CoV-2 spike (S) protein binds to angiotensin-converting enzyme 2 (ACE-2), that promotes cellular entry of this virus in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2). Today, there are no vaccines and/or effective drugs against the SARS-CoV-2 coronavirus. Thus, manipulation of key entry genes of this virus especially in lung cancer patients could be one of the best approaches to manage SARS-CoV-2 infection in this group of patients. We herein provide a comprehensive and up-to-date overview of the role of ACE-2 and TMPRSS2 genes, as key entry elements as well as therapeutic targets for SARS-CoV-2 infection, which can help to better understand the applications and capacities of various remedial approaches for infected individuals, especially those with lung cancer.

| S-EPMC7464614 | biostudies-literature

Current Potential Therapeutic Approaches against SARS-CoV-2: A Review.

Project description:The ongoing SARS-CoV-2 pandemic is a serious threat to public health worldwide and, to date, no effective treatment is available. Thus, we herein review the pharmaceutical approaches to SARS-CoV-2 infection treatment. Numerous candidate medicines that can prevent SARS-CoV-2 infection and replication have been proposed. These medicines include inhibitors of serine protease TMPRSS2 and angiotensin converting enzyme 2 (ACE2). The S protein of SARS-CoV-2 binds to the receptor in host cells. ACE2 inhibitors block TMPRSS2 and S protein priming, thus preventing SARS-CoV-2 entry to host cells. Moreover, antiviral medicines (including the nucleotide analogue remdesivir, the HIV protease inhibitors lopinavir and ritonavir, and wide-spectrum antiviral antibiotics arbidol and favipiravir) have been shown to reduce the dissemination of SARS-CoV-2 as well as morbidity and mortality associated with COVID-19.

| S-EPMC8615922 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data