Signaling network analysis reveals fostamatinib as a potential drug to control platelet hyperactivation during SARS-CoV-2 infection

Özge Osmanoglu; Shishir K Gupta; Anna Almasi; Seray Yagci; Mugdha Srivastava; Gabriel H M Araujo; Zoltan Nagy; Johannes Balkenhol; Thomas Dandekar

doi:10.3389/fimmu.2023.1285345

Signaling network analysis reveals fostamatinib as a potential drug to control platelet hyperactivation during SARS-CoV-2 infection

Front Immunol. 2023 Dec 21:14:1285345. doi: 10.3389/fimmu.2023.1285345. eCollection 2023.

Authors

Özge Osmanoglu^#¹, Shishir K Gupta^#^{2

3}, Anna Almasi¹, Seray Yagci¹, Mugdha Srivastava^{4

5}, Gabriel H M Araujo⁶, Zoltan Nagy⁶, Johannes Balkenhol^{1

7}, Thomas Dandekar^{1

8}

Affiliations

¹ Functional Genomics & Systems Biology Group, Department of Bioinformatics, Biocenter, University of Wuerzburg, Wuerzburg, Germany.
² Evolutionary Genomics Group, Center for Computational and Theoretical Biology, University of Würzburg, Würzburg, Germany.
³ Institute of Botany, Heinrich Heine University, Düsseldorf, Germany.
⁴ Core Unit Systems Medicine, University of Wuerzburg, Wuerzburg, Germany.
⁵ Algorithmic Bioinformatics, Department of Computer Science, Heinrich Heine University, Düsseldorf, Germany.
⁶ University Hospital Würzburg, Institute of Experimental Biomedicine, Würzburg, Germany.
⁷ Chair of Molecular Microscopy, Rudolf Virchow Center for Integrative and Translation Bioimaging, University of Würzburg, Würzburg, Germany.
⁸ European Molecular Biology Laboratory (EMBL) Heidelberg, BioComputing Unit, Heidelberg, Germany.

^# Contributed equally.

Abstract

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/.

Keywords: COVID-19; SARS-CoV-2; controllability; drug repurposing; fostamatinib; platelet; signaling network.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aminopyridines
COVID-19*
Critical Care
Humans
Oxazines
Pyridines
SARS-CoV-2

Substances

fostamatinib
Aminopyridines
Oxazines
Pyridines

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The authors gratefully acknowledge the support by the Deutsche Forschungsgemeinschaft (DFG) project number 3 74031971, SFB/TRR240/Z2 “platelets” (ÖO, JB, and TD; network model of platelets) and by the new grant 492620490 -SFB 1583/INF (ÖO, JB, and TD; studying hyperactivation of platelets in infection).