Drug-target identification in COVID-19 disease mechanisms using computational systems biology approaches

Anna Niarakis; Marek Ostaszewski; Alexander Mazein; Inna Kuperstein; Martina Kutmon; Marc E Gillespie; Akira Funahashi; Marcio Luis Acencio; Ahmed Hemedan; Michael Aichem; Karsten Klein; Tobias Czauderna; Felicia Burtscher; Takahiro G Yamada; Yusuke Hiki; Noriko F Hiroi; Finterly Hu; Nhung Pham; Friederike Ehrhart; Egon L Willighagen; Alberto Valdeolivas; Aurelien Dugourd; Francesco Messina; Marina Esteban-Medina; Maria Peña-Chilet; Kinza Rian; Sylvain Soliman; Sara Sadat Aghamiri; Bhanwar Lal Puniya; Aurélien Naldi; Tomáš Helikar; Vidisha Singh; Marco Fariñas Fernández; Viviam Bermudez; Eirini Tsirvouli; Arnau Montagud; Vincent Noël; Miguel Ponce-de-Leon; Dieter Maier; Angela Bauch; Benjamin M Gyori; John A Bachman; Augustin Luna; Janet Piñero; Laura I Furlong; Irina Balaur; Adrien Rougny; Yohan Jarosz; Rupert W Overall; Robert Phair; Livia Perfetto; Lisa Matthews; Devasahayam Arokia Balaya Rex; Marija Orlic-Milacic; Luis Cristobal Monraz Gomez; Bertrand De Meulder; Jean Marie Ravel; Bijay Jassal; Venkata Satagopam; Guanming Wu; Martin Golebiewski; Piotr Gawron; Laurence Calzone; Jacques S Beckmann; Chris T Evelo; Peter D'Eustachio; Falk Schreiber; Julio Saez-Rodriguez; Joaquin Dopazo; Martin Kuiper; Alfonso Valencia; Olaf Wolkenhauer; Hiroaki Kitano; Emmanuel Barillot; Charles Auffray; Rudi Balling; Reinhard Schneider; COVID-19 Disease Map Community

doi:10.3389/fimmu.2023.1282859

Drug-target identification in COVID-19 disease mechanisms using computational systems biology approaches

Front Immunol. 2024 Feb 13:14:1282859. doi: 10.3389/fimmu.2023.1282859. eCollection 2023.

Authors

Anna Niarakis^{1

2}, Marek Ostaszewski³, Alexander Mazein³, Inna Kuperstein^{4

5

6}, Martina Kutmon⁷, Marc E Gillespie^{8

9}, Akira Funahashi¹⁰, Marcio Luis Acencio³, Ahmed Hemedan³, Michael Aichem¹¹, Karsten Klein¹¹, Tobias Czauderna¹², Felicia Burtscher³, Takahiro G Yamada¹⁰, Yusuke Hiki¹³, Noriko F Hiroi^{14

15}, Finterly Hu^{7

16}, Nhung Pham^{7

16}, Friederike Ehrhart¹⁶, Egon L Willighagen¹⁶, Alberto Valdeolivas¹⁷, Aurelien Dugourd¹⁷, Francesco Messina¹⁸, Marina Esteban-Medina^{19

20}, Maria Peña-Chilet^{19

20

21}, Kinza Rian¹⁹, Sylvain Soliman², Sara Sadat Aghamiri²², Bhanwar Lal Puniya²², Aurélien Naldi², Tomáš Helikar²², Vidisha Singh¹, Marco Fariñas Fernández²³, Viviam Bermudez²³, Eirini Tsirvouli²³, Arnau Montagud²⁴, Vincent Noël^{4

5

6}, Miguel Ponce-de-Leon²⁴, Dieter Maier²⁵, Angela Bauch²⁵, Benjamin M Gyori²⁶, John A Bachman²⁶, Augustin Luna^{27

28}, Janet Piñero^{29

30}, Laura I Furlong^{29

30}, Irina Balaur³, Adrien Rougny^{31

32}, Yohan Jarosz³, Rupert W Overall³³, Robert Phair³⁴, Livia Perfetto³⁵, Lisa Matthews³⁶, Devasahayam Arokia Balaya Rex³⁷, Marija Orlic-Milacic⁸, Luis Cristobal Monraz Gomez^{4

5

6}, Bertrand De Meulder³⁸, Jean Marie Ravel^{4

5

6}, Bijay Jassal⁸, Venkata Satagopam^{3

39}, Guanming Wu⁴⁰, Martin Golebiewski⁴¹, Piotr Gawron³, Laurence Calzone^{4

5

6}, Jacques S Beckmann⁴², Chris T Evelo¹⁶, Peter D'Eustachio³⁶, Falk Schreiber^{11

43}, Julio Saez-Rodriguez¹⁷, Joaquin Dopazo^{19

20

21

44}, Martin Kuiper²³, Alfonso Valencia^{24

45}, Olaf Wolkenhauer^{46

47}, Hiroaki Kitano⁴⁸, Emmanuel Barillot^{4

5

6}, Charles Auffray³⁸, Rudi Balling⁴⁹, Reinhard Schneider³; COVID-19 Disease Map Community

Affiliations

¹ Université Paris-Saclay, Laboratoire Européen de Recherche pour la Polyarthrite rhumatoïde - Genhotel, Univ Evry, Evry, France.
² Lifeware Group, Inria, Saclay-île de France, Palaiseau, France.
³ Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
⁴ Institut Curie, P.S.L. Research University, Paris, France.
⁵ INSERM, Paris, France.
⁶ MINES ParisTech, PSL Research University, CBIO-Centre for Computational Biology, Paris, France.
⁷ Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, Netherlands.
⁸ Ontario Institute for Cancer Research, Toronto, ON, Canada.
⁹ St. John's University, Queens, NY, United States.
¹⁰ Department of Biosciences and Informatics, Keio University, Kanagawa, Japan.
¹¹ Department of Computer and Information Science, University of Konstanz, Konstanz, Germany.
¹² Faculty of Applied Computer Sciences & Biosciences, University of Applied Sciences Mittweida, Mittweida, Germany.
¹³ Center for Biosciences and Informatics, Graduate School of Fundamental Science and Technology, Keio University, Kanagawa, Japan.
¹⁴ Faculty of Creative Engineering, Kanagawa Institute of Technology, Kanagawa, Japan.
¹⁵ Keio University School of Medicine, Tokyo, Japan.
¹⁶ Department of Bioinformatics - BiGCaT, NUTRIM, Maastricht University, Maastricht, Netherlands.
¹⁷ Institute for Computational Biomedicine, Heidelberg University, Faculty of Medicine, Heidelberg University Hospital, Bioquant, Heidelberg, Germany.
¹⁸ Department of Epidemiology, Preclinical Research and Advanced Diagnostic, National Institute for Infectious Diseases' Lazzaro Spallanzani' - IRCCS, Rome, Italy.
¹⁹ Computational Medicine Platform, Andalusian Public Foundation Progress and Health-FPS, Sevilla, Spain.
²⁰ Computational Systems Medicine, Institute of Biomedicine of Seville (IBIS), Hospital Virgen del Rocío, Sevilla, Spain.
²¹ Bioinformatics in Rare Diseases (BiER), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), FPS, Hospital Virgen del Rocio, Seville, Spain.
²² Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE, United States.
²³ Department of Biology, Norwegian University of Science and Technology, Trondheim, Norway.
²⁴ Barcelona Supercomputing Center (BSC.), Barcelona, Spain.
²⁵ Labvantage-Biomax GmbH, Planegg, Germany.
²⁶ Harvard Medical School, Laboratory of Systems Pharmacology, Boston, MA, United States.
²⁷ Computational Biology Branch, National Library of Medicine, Bethesda, MD, United States.
²⁸ Department of Systems Biology, Harvard Medical School, Boston, MA, United States.
²⁹ Medbioinformatics Solutions SL, Barcelona, Spain.
³⁰ Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM), Dept. of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Spain.
³¹ Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), Aomi, Tokyo, Japan.
³² Com. Bio Big Data Open Innovation Lab. (CBBD-OIL), AIST, Aomi, Tokyo, Japan.
³³ Institute for Biology, Humboldt University of Berlin, Berlin, Germany.
³⁴ Integrative Bioinformatics, Inc., Mountain View, CA, United States.
³⁵ Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, Rome, Italy.
³⁶ Department of Biochemistry & Molecular Pharmacology, NYU. Langone Medical Center, New York, NY, United States.
³⁷ Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Derlakatte, Mangalore, India.
³⁸ Association E.I.S.B.M, Brignais, France.
³⁹ Frankfurt Institute for Advanced Studies, Johann Wolfgang Goethe-Universität Frankfurt, Frankfurt am Main, Germany.
⁴⁰ Oregon Health Sciences University, Portland, OR, United States.
⁴¹ Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany.
⁴² University of Lausanne, Lausanne, Switzerland.
⁴³ Faculty of Information Technology, Monash University, Clayton, Victoria, VIC, Australia.
⁴⁴ FPS/ELIXIR-es, Hospital Virgen del Rocío, Sevilla, Spain.
⁴⁵ I.C.R.E.A., Pg. Lluís Companys 23, Barcelona, Spain.
⁴⁶ Department of Systems Biology & Bioinformatics, University of Rostock, Rostock, Germany.
⁴⁷ Leibniz Institute for Food Systems Biology, at the Technical University Munich, Munich, Germany.
⁴⁸ Systems Biology Institute, Tokyo, Japan.
⁴⁹ Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany.

Abstract

Introduction: The COVID-19 Disease Map project is a large-scale community effort uniting 277 scientists from 130 Institutions around the globe. We use high-quality, mechanistic content describing SARS-CoV-2-host interactions and develop interoperable bioinformatic pipelines for novel target identification and drug repurposing.

Methods: Extensive community work allowed an impressive step forward in building interfaces between Systems Biology tools and platforms. Our framework can link biomolecules from omics data analysis and computational modelling to dysregulated pathways in a cell-, tissue- or patient-specific manner. Drug repurposing using text mining and AI-assisted analysis identified potential drugs, chemicals and microRNAs that could target the identified key factors.

Results: Results revealed drugs already tested for anti-COVID-19 efficacy, providing a mechanistic context for their mode of action, and drugs already in clinical trials for treating other diseases, never tested against COVID-19.

Discussion: The key advance is that the proposed framework is versatile and expandable, offering a significant upgrade in the arsenal for virus-host interactions and other complex pathologies.

Keywords: SARS-CoV-2; disease maps; dynamic models; large-scale community effort; mechanistic models; systems biology; systems medicine.

Copyright © 2024 Niarakis, Ostaszewski, Mazein, Kuperstein, Kutmon, Gillespie, Funahashi, Acencio, Hemedan, Aichem, Klein, Czauderna, Burtscher, Yamada, Hiki, Hiroi, Hu, Pham, Ehrhart, Willighagen, Valdeolivas, Dugourd, Messina, Esteban-Medina, Peña-Chilet, Rian, Soliman, Aghamiri, Puniya, Naldi, Helikar, Singh, Fernández, Bermudez, Tsirvouli, Montagud, Noël, Ponce-de-Leon, Maier, Bauch, Gyori, Bachman, Luna, Piñero, Furlong, Balaur, Rougny, Jarosz, Overall, Phair, Perfetto, Matthews, Rex, Orlic-Milacic, Gomez, De Meulder, Ravel, Jassal, Satagopam, Wu, Golebiewski, Gawron, Calzone, Beckmann, Evelo, D’Eustachio, Schreiber, Saez-Rodriguez, Dopazo, Kuiper, Valencia, Wolkenhauer, Kitano, Barillot, Auffray, Balling, Schneider and the COVID-19 Disease Map Community.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

COVID-19*
Computer Simulation
Drug Repositioning
Humans
SARS-CoV-2
Systems Biology

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. AN acknowledges support from SANOFI-AVENTIS R&D via the CIFRE contract, n° 2020/0766. MK, FH, NP, FE, and CE acknowledge the support of the ZonMw COVID-19 programme (Grant No. 10430012010015). JD Spanish Ministry of Science and Innovation (Grant no. PID2020-117979RB-I00) and Instituto de Salud Carlos III (Grant no. IMP/00019). MAi, KK, FS: Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - Project-ID 251654672 - TRR 161 and under Germany’s Excellence Strategy - EXC 2117 - 422037984. FM: “5 per 1000–2021” grant of the Italian Ministry of Health (Grant No. 5M-2021-23683787) and European Commission with HORIZON programme, BY-COVID project (Grant No. 101046203—BY-COVID). National Institute for Infectious Diseases Lazzaro Spallanzani–IRCCS received financial support from the Italian Ministry of Health grant “Ricerca Corrente”. JP, LF: IMI2-JU grants, resources which are composed of financial contributions from the European Union’s Horizon 2020 Research and Innovation Programme and EFPIA [GA: 777365 eTRANSAFE], and the EU H2020 Programme [GA:964537 RISKHUNT3R]; Project 001-P-001647—Valorisation of EGA for Industry and Society funded by the European Regional Development Fund (ERDF) and Generalitat de Catalunya; Institute of Health Carlos III (project IMPaCT-Data, exp. IMP/00019), co-funded by the European Union, European Regional Development Fund (ERDF, “A way to make Europe”). AMo, MP and AV acknowledge the support of the European Commission under the INFORE project (H2020-ICT-825070) and the PerMedCoE (H2020-ICT-951773). Contributions by TH and BLP were supported by NIH grant #R35GM119770 to TH. MaGo acknowledges funding from Deutsche Forschungsgemeinschaft (DFG) through grants no. 442326535 (NFDI4Health) and 451265285 (NFDI4Health Task Force COVID-19), from the European Commission through the Horizon 2020 framework program under grant no. 825843 (EU-STANDS4PM) and through the Digital Europe program under grant no. 101083771 (EDITH), as well as from the Klaus Tschira Foundation. AL acknowledges support from the Intramural Research Program of the National Library of Medicine (NLM), National Institutes of Health (NIH).