The key role of Calpain in COVID-19 as a therapeutic strategy

Juibari, Aref Doozandeh; Rezadoost, Mohammad Hossein; Soleimani, Masoud

doi:10.1007/s10787-022-01002-1

Cited by 10 publications

(6 citation statements)

References 93 publications

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“…Under normal conditions, autophagy suppresses inflammatory factors, but defective autophagy seen in SARS-CoV-2 reveals that the virus and viral-altered processes may uncontrollably stimulate inflammatory pathways [67,79,95]. One example is that ROS accumulation stimulates various mechanisms of inflammation, including inflammasomes and calpain, to produce IL-1B and IL-1a, respectively [96][97][98]. They also increase RIG-I-like receptors to enhance type-I IFN production.…”

Section: Autophagy and The Replication Of Sars-cov-2mentioning

confidence: 99%

Pathogenesis and Mechanisms of SARS-CoV-2 Infection in the Intestine, Liver, and Pancreas

Khreefa

Barbier

Koksal

et al. 2023

Cells

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The novel coronavirus, SARS-CoV-2, rapidly spread worldwide, causing an ongoing global pandemic. While the respiratory system is the most common site of infection, a significant number of reported cases indicate gastrointestinal (GI) involvement. GI symptoms include anorexia, abdominal pain, nausea, vomiting, and diarrhea. Although the mechanisms of GI pathogenesis are still being examined, viral components isolated from stool samples of infected patients suggest a potential fecal–oral transmission route. In addition, viral RNA has been detected in blood samples of infected patients, making hematologic dissemination of the virus a proposed route for GI involvement. Angiotensin-converting enzyme 2 (ACE2) receptors serve as the cellular entry mechanism for the virus, and these receptors are particularly abundant throughout the GI tract, making the intestine, liver, and pancreas potential extrapulmonary sites for infection and reservoirs sites for developing mutations and new variants that contribute to the uncontrolled spread of the disease and resistance to treatments. This transmission mechanism and the dysregulation of the immune system play a significant role in the profound inflammatory and coagulative cascades that contribute to the increased severity and risk of death in several COVID-19 patients. This article reviews various potential mechanisms of gastrointestinal, liver, and pancreatic injury.

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Section: Autophagy and The Replication Of Sars-cov-2mentioning

confidence: 99%

Pathogenesis and Mechanisms of SARS-CoV-2 Infection in the Intestine, Liver, and Pancreas

Khreefa

Barbier

Koksal

et al. 2023

Cells

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“… 15 , 16 Although the detailed mechanism is unknown, evidence suggested that calpains, another class of intracellular calcium-activated cysteine proteases, also play a key role in the early steps of the coronaviral life cycle. 17 , 18 As such, both proteases are potential targets for broad-spectrum antiviral intervention.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, there have been several reports on the effective coronavirus inhibitors that target host CTSL and/or CAPN1 (Supplementary Scheme S1). 17,[28][29][30] Most of them were identified through drug repurposing efforts. Several promising repurposed drugs are undergoing clinical trials for the treatment of COVID-19, e.g., CTSL inhibitor SLV213 (https:// clinicaltrials.gov/ct2/show/NCT04843787), which was originally developed as a therapeutic for the treatment of Chagas disease, 31 and calpains inhibitor BLD2660 (https://clinicaltrials.gov/ct2/show/ results/NCT04334460), which was originally developed for the treatment of fibrotic diseases.…”

Section: Introductionmentioning

confidence: 99%

Structure-based design of pan-coronavirus inhibitors targeting host cathepsin L and calpain-1

Xie,

Lan,

Zhao

et al. 2024

Sig Transduct Target Ther

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Respiratory disease caused by coronavirus infection remains a global health crisis. Although several SARS-CoV-2-specific vaccines and direct-acting antivirals are available, their efficacy on emerging coronaviruses in the future, including SARS-CoV-2 variants, might be compromised. Host-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging coronaviruses. Cathepsin L (CTSL) and calpain-1 (CAPN1) are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune response. Here, two peptidomimetic α-ketoamide compounds, 14a and 14b, were identified as potent dual target inhibitors against CTSL and CAPN1. The X-ray crystal structures of human CTSL and CAPN1 in complex with 14a and 14b revealed the covalent binding of α-ketoamide groups of 14a and 14b to C25 of CTSL and C115 of CAPN1. Both showed potent and broad-spectrum anticoronaviral activities in vitro, and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern (VOCs) with EC50 values ranging from 0.80 to 161.7 nM in various cells. Preliminary mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral entrance. Moreover, 14a and 14b exhibited good oral pharmacokinetic properties in mice, rats and dogs, and favorable safety in mice. In addition, both 14a and 14b treatments demonstrated potent antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse model. And 14b also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60%. Further evaluation showed that 14a and 14b exhibited excellent anti-inflammatory effects in Raw 264.7 mouse macrophages and in mice with acute pneumonia. Taken together, these results suggested that 14a and 14b are promising drug candidates, providing novel insight into developing pan-coronavirus inhibitors with antiviral and anti-inflammatory properties.

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“…Current knowledge suggests that calpain 1 may play a dual role in the development of ARDS: a direct cytopathic effect and an increase in the inflammatory response through direct activation of IL-33, which contributes to the development of cytokine storm and ARDS. In addition, the role of calpain 1 has also been described in terms of the internalization of the virus into cells, and its inhibitors are placed in the context of potential drugs for the treatment of COVID-19 [30,31].…”

Section: Introductionmentioning

confidence: 99%

The Correlation of Serum Calpain 1 Activity and Concentrations of Interleukin 33 in COVID-19 Acute Respiratory Distress Syndrome

Loinjak,

Mihić,

Smolić

et al. 2023

Biomedicines

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Acute respiratory distress syndrome (ARDS) is one of the most severe complications of the COVID-19 disease. The role of IL-33 and calpain 1 was previously described in lung infections and lung tissue damage. Our study examined the association between serum calpain 1 activity and IL-33 concentration in patients with COVID-19 ARDS. In the research, we included 80 subjects who had COVID-19 pneumonia and divided them into 2 groups: 40 subjects with ARDS and 40 subjects without ARDS. The basis of the research was the collection of subjects’ data and the sampling of peripheral venous blood. The concentration of IL-33 was determined by the ELISA method and the activity of calpain 1 by the fluorometry method. Our research showed elevated calpain 1 activity and IL-33 concentration in the serum of COVID-19 patients who developed ARDS compared to those who did not develop ARDS and a positive correlation between them was established. Further, a positive correlation was established between the examined parameters and the severity of the disease, proinflammatory markers, and the use of mechanical ventilation. These results indicate a possible association and role of calpain 1 and IL-33 with the development of ARDS in COVID-19 patients.

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The key role of Calpain in COVID-19 as a therapeutic strategy

Cited by 10 publications

References 93 publications

Pathogenesis and Mechanisms of SARS-CoV-2 Infection in the Intestine, Liver, and Pancreas

Pathogenesis and Mechanisms of SARS-CoV-2 Infection in the Intestine, Liver, and Pancreas

Structure-based design of pan-coronavirus inhibitors targeting host cathepsin L and calpain-1

The Correlation of Serum Calpain 1 Activity and Concentrations of Interleukin 33 in COVID-19 Acute Respiratory Distress Syndrome

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