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A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors
Published on: June 8, 2022
Signaling network analysis reveals fostamatinib as a potential drug to control platelet hyperactivation during
Özge Osmanoglu1, Shishir K Gupta2,3, Anna Almasi1
1Functional Genomics & Systems Biology Group, Department of Bioinformatics, Biocenter, University of Wuerzburg, Wuerzburg, Germany.
Insights
COVID-19 patients admitted to the intensive care unit (ICU) experience more pro-thrombotic events due to platelet hyperactivation. Fostamatinib is identified as a potential drug to control these events by targeting key proteins in COVID-19 patients.
Area of Science:
- * Molecular Biology
- * Systems Biology
- * Pharmacology
Background:
- * Pro-thrombotic events are a major cause of intensive care unit (ICU) admission in COVID-19 patients.
- * The precise signaling mechanisms driving platelet hyperactivation in COVID-19 remain unclear.
- * Understanding these mechanisms is crucial for developing targeted therapies.
Purpose of the Study:
- * To elucidate the signaling events and network control underlying platelet hyperactivation in COVID-19.
- * To compare platelet transcriptome data between healthy donors, non-ICU, and ICU COVID-19 patients.
- * To identify potential drug targets and repurpose existing medications for managing COVID-19-related thrombosis.
Main Methods:
- * Comparative analysis of platelet transcriptome data.
- * Construction of signaling network models integrating transcriptome data with a global human signaling network.
- * Investigation of platelet hyperactivation control cascades and identification of indispensable proteins.
- * Scrutiny of FDA-approved drugs targeting identified indispensable proteins.
Main Results:
- * Significantly higher platelet network control observed in ICU COVID-19 patients compared to non-ICU patients.
- * Identification of key subnetworks and indispensable proteins critical for controlling platelet hyperactivity.
- * Fostamatinib identified as a potent candidate drug for preventing thrombosis in COVID-19 patients.
- * Network analysis revealed distinct states in non-ICU and ICU patients, guiding drug prioritization.
Conclusions:
- * SARS-CoV-2 infection dysregulates host platelets by targeting critical proteins involved in platelet activity control.
- * Drug repurposing, specifically with fostamatinib, offers a promising strategy for managing COVID-19-associated platelet hyperactivation and thrombosis.
- * The study provides specific pharmacological recommendations tailored to individual patient network states.
Introduction:
Pro-thrombotic events are one of the prevalent causes of intensive care unit (ICU) admissions among COVID-19 patients, although the signaling events in the stimulated platelets are still unclear.
Methods:
We conducted a comparative analysis of platelet transcriptome data from healthy donors, ICU, and non-ICU COVID-19 patients to elucidate these mechanisms. To surpass previous analyses, we constructed models of involved networks and control cascades by integrating a global human signaling network with transcriptome data. We investigated the control of platelet hyperactivation and the specific proteins involved.
Results:
Our study revealed that control of the platelet network in ICU patients is significantly higher than in non-ICU patients. Non-ICU patients require control over fewer proteins for managing platelet hyperactivity compared to ICU patients. Identification of indispensable proteins highlighted key subnetworks, that are targetable for system control in COVID-19-related platelet hyperactivity. We scrutinized FDA-approved drugs targeting indispensable proteins and identified fostamatinib as a potent candidate for preventing thrombosis in COVID-19 patients.
Discussion:
Our findings shed light on how SARS-CoV-2 efficiently affects host platelets by targeting indispensable and critical proteins involved in the control of platelet activity. We evaluated several drugs for specific control of platelet hyperactivity in ICU patients suffering from platelet hyperactivation. The focus of our approach is repurposing existing drugs for optimal control over the signaling network responsible for platelet hyperactivity in COVID-19 patients. Our study offers specific pharmacological recommendations, with drug prioritization tailored to the distinct network states observed in each patient condition. Interactive networks and detailed results can be accessed at https://fostamatinib.bioinfo-wuerz.eu/.
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