D020 Role of Cellular Caspases and Therapeutic Potential of a Pan-Caspase Inhibitor, Emricasan, in Covid-19.

Alpan, Oral; Gupta, Raavi; Latterich, Martin; Hubka, M.; Bukhari, Zaheer; Ndhlovu, Lishomwa C.

doi:10.1016/j.anai.2021.08.051

Cited by 3 publications

(3 citation statements)

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“…Targeting pyroptosis or apoptosis induced by inflammasomes is suggested to be a promising strategy in COVID-19 and other disease treatment [ 1 , 13 , 20 , 40 ]. Focusing on exploring the efficient control strategy of the transducers is therefore a significant issue [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Caspase-1 and Gasdermin D Afford the Optimal Targets with Distinct Switching Strategies in NLRP1b Inflammasome-Induced Cell Death

Zhang

Yin

et al. 2022

Research

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Inflammasomes are essential complexes of innate immune system, which form the first line of host defense against pathogens. Mounting evidence accumulates that inflammasome signaling is highly correlated with coronavirus disease 2019 (COVID-19). However, there remains a significant gap in our understanding of the regulatory mechanism of inflammasome signaling. Combining mathematical modeling with experimental analysis of NLRP1b inflammasome signaling, we found that only the expression levels of caspase-1 and GSDMD have the potential to individually switch cell death modes. Reduction of caspase-1 or GSDMD switches cell death from pyroptosis to apoptosis. Caspase-1 and GSDMD present different thresholds and exert distinct pathway choices in switching death modes. Pyroptosis switches to apoptosis with an extremely low threshold level of caspase-1, but with a high threshold of GSDMD. Caspase-1-impaired cells employ ASC-caspase-8-dependent pathway for apoptosis, while GSDMD-impaired cells primarily utilize caspase-1-dependent pathway. Additionally, caspase-1 and GSDMD can severally ignite the cooccurrence of pyroptosis and apoptosis. Landscape topography unravels that the cooccurrence is dramatically different in caspase-1- and GSDMD-impaired cells. Besides pyroptosis state and apoptosis state, a potential new “coexisting” state in single cells is proposed when GSDMD acts as the driving force of the landscape. The “seesaw model” is therefore proposed, which can well describe the death states that are controlled by caspase-1 or GSDMD in single cells. Our study sheds new light on NLRP1b inflammasome signaling and uncovers the switching mechanisms among various death modes, providing potential clues to guide the development of more rational control strategies for diseases.

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Section: Discussionmentioning

confidence: 99%

Caspase-1 and Gasdermin D Afford the Optimal Targets with Distinct Switching Strategies in NLRP1b Inflammasome-Induced Cell Death

Zhang

Yin

et al. 2022

Research

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“…It has also enabled innovation by the rapid identification of new biomarkers facilitating the development of novel therapies. One example is the speedy identification of the role of caspases in COVID-19 pathogenesis, development of this as a laboratory developed test, verification of the findings in clinical samples which led to the completion of a Phase 1 study in COVID in 2021 using a pan-caspase inhibitor ( 45 ). Innovations in diagnostics have helped advance many therapies.…”

Section: Basic Methodological Aspect Of Batmentioning

confidence: 99%

Towards an FDA-cleared basophil activation test

Alpan¹,

Wasserman

Kim³

et al. 2023

Front. Allergy

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Food allergy is a global health problem affecting up to 10% of the world population. Accurate diagnosis of food allergies, however, is still a major challenge in medical offices and for patients seeking alternative avenues of diagnosis. A flawless test to confirm or rule out a food allergy does not exist. The lack of optimum testing methods to establish precise clinical correlations remains a major obstacle to effective treatment. Certain IgE measurement methods, including component testing, have received FDA clearance, but they have been used primarily as an analytical tool and not to establish clinical correlations. Most allergy tests are still carried out within the laboratory, and skin tests outside a laboratory setting that are used for food allergy diagnosis rely on non-standardized allergens, according to the FDA definition. Epitope mapping and basophil activation test (BAT) have recently been proposed as a means of establishing better clinical correlations. Yet neither have received FDA clearance for widespread distribution. Of the two methods, the BAT has the advantage of being a functional assay. Over the past few years, several large private practice groups in the United States, have developed BAT as a clinical assay and have started using it in patient care. Given this clinical experience, the vast number of papers published on BAT (more than 1,400 as of 2022) and the trend toward increasing FDA regulation, it is essential to understand the roadmap for regulatory clearance of this assay.

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“…A tolerability study was conducted by Raavi Gupta (NCT04803227 [ 69 ]) in 50 symptomatic patients with mild COVID-19 by administering EMR at 25 mg BID dosing for 14 days, with a 1:1 active:placebo ratio of mild COVID-19 patients receiving standard care therapy [ 69 ]. Although EMR has been extensively studied in humans in phase-1 and phase-2 studies, where it has shown excellent safety and tolerance profiles, it had not been used in the COVID-19 setting, therefore necessitating an initial safety and tolerability study [ 40 , 70 , 71 ].…”

Section: Caspase Inhibitorsmentioning

confidence: 99%

Small Molecules for the Treatment of Long-COVID-Related Vascular Damage and Abnormal Blood Clotting: A Patent-Based Appraisal

Samarelli,

Graziano,

Gambacorta

et al. 2024

Viruses

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People affected by COVID-19 are exposed to, among others, abnormal clotting and endothelial dysfunction, which may result in deep vein thrombosis, cerebrovascular disorders, and ischemic and non-ischemic heart diseases, to mention a few. Treatments for COVID-19 include antiplatelet (e.g., aspirin, clopidogrel) and anticoagulant agents, but their impact on morbidity and mortality has not been proven. In addition, due to viremia-associated interconnected prothrombotic and proinflammatory events, anti-inflammatory drugs have also been investigated for their ability to mitigate against immune dysregulation due to the cytokine storm. By retrieving patent literature published in the last two years, small molecules patented for long-COVID-related blood clotting and hematological complications are herein examined, along with supporting evidence from preclinical and clinical studies. An overview of the main features and therapeutic potentials of small molecules is provided for the thromboxane receptor antagonist ramatroban, the pan-caspase inhibitor emricasan, and the sodium–hydrogen antiporter 1 (NHE-1) inhibitor rimeporide, as well as natural polyphenolic compounds.

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D020 Role of Cellular Caspases and Therapeutic Potential of a Pan-Caspase Inhibitor, Emricasan, in Covid-19.

Cited by 3 publications

References 0 publications

Caspase-1 and Gasdermin D Afford the Optimal Targets with Distinct Switching Strategies in NLRP1b Inflammasome-Induced Cell Death

Caspase-1 and Gasdermin D Afford the Optimal Targets with Distinct Switching Strategies in NLRP1b Inflammasome-Induced Cell Death

Towards an FDA-cleared basophil activation test

Small Molecules for the Treatment of Long-COVID-Related Vascular Damage and Abnormal Blood Clotting: A Patent-Based Appraisal

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