Application of the PHENotype SIMulator for rapid identification of potential candidates in effective COVID-19 drug repurposing

Naomi I Maria; Rosaria Valentina Rapicavoli; Salvatore Alaimo; Evelyne Bischof; Alessia Stasuzzo; Jantine A C Broek; Alfredo Pulvirenti; Bud Mishra; Ashley J Duits; Alfredo Ferro; RxCOVEA Framework

doi:10.1016/j.heliyon.2023.e14115

Application of the PHENotype SIMulator for rapid identification of potential candidates in effective COVID-19 drug repurposing

Heliyon. 2023 Mar;9(3):e14115. doi: 10.1016/j.heliyon.2023.e14115. Epub 2023 Mar 6.

Authors

Naomi I Maria^{1

2

3

4

5}, Rosaria Valentina Rapicavoli^{6

7}, Salvatore Alaimo⁷, Evelyne Bischof^{8

9

10}, Alessia Stasuzzo¹¹, Jantine A C Broek¹, Alfredo Pulvirenti⁷, Bud Mishra^{1

12}, Ashley J Duits^{4

13

14}, Alfredo Ferro⁷; RxCOVEA Framework

Affiliations

¹ Department of Computer Science, Mathematics, Engineering and Cell Biology, Courant Institute, Tandon and School of Medicine, New York University, New York, USA.
² Institute of Molecular Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA.
³ Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra, Northwell Health, Manhasset, NY, USA.
⁴ Red Cross Blood Bank Foundation Curaçao, Willemstad, Curaçao.
⁵ Department of Medical Microbiology and Immunology, St. Antonius Ziekenhuis, Niewegein, the Netherlands.
⁶ Department of Physics and Astronomy, University of Catania, Italy.
⁷ Bioinformatics Unit, Department of Clinical and Experimental Medicine, University of Catania, Italy.
⁸ Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini, Naples, Italy.
⁹ School of Clinical Medicine, Shanghai University of Medicine and Health Sciences, Pudong, Shanghai, China.
¹⁰ Insilico Medicine, Hong Kong Special Administrative Region, China.
¹¹ Department of Chemical Sciences, University of Catania, Italy.
¹² Simon Center for Quantitative Biology, Cold Spring Harbor Lab, Long Island, USA.
¹³ Curaçao Biomedical Health Research Institute, Willemstad, Curaçao.
¹⁴ Institute for Medical Education, University Medical Center Groningen, Groningen, the Netherlands.

Abstract

The current, rapidly diversifying pandemic has accelerated the need for efficient and effective identification of potential drug candidates for COVID-19. Knowledge on host-immune response to SARS-CoV-2 infection, however, remains limited with few drugs approved to date. Viable strategies and tools are rapidly arising to address this, especially with repurposing of existing drugs offering significant promise. Here we introduce a systems biology tool, the PHENotype SIMulator, which -by leveraging available transcriptomic and proteomic databases-allows modeling of SARS-CoV-2 infection in host cells in silico to i) determine with high sensitivity and specificity (both>96%) the viral effects on cellular host-immune response, resulting in specific cellular SARS-CoV-2 signatures and ii) utilize these cell-specific signatures to identify promising repurposable therapeutics. Powered by this tool, coupled with domain expertise, we identify several potential COVID-19 drugs including methylprednisolone and metformin, and further discern key cellular SARS-CoV-2-affected pathways as potential druggable targets in COVID-19 pathogenesis.

Keywords: 2DG, 2-Deoxy-Glucose; ACE2, Angiotensin-converting enzyme 2; COVID-19; COVID-19, Coronavirus disease 2019; Caco-2, Human colon epithelial carcinoma cell line; Calu-3, Epithelial cell line; Cellular SARS-CoV-2 signatures; Cellular host-immune response; Cellular simulation models; DEGs, Differentially Expressed Genes; DEPs, Differentially expressed proteins; Drug repurposing; HCQ-CQ, (Hydroxy)chloroquine; IFN, Interferon; ISGs, IFN-stimulated genes; MITHrIL, Mirna enrIched paTHway Impact anaLysis; MOI, Multiplicity of infection; MP, Methylprednisolone; NHBE, Normal human bronchial epithelial cells; PHENSIM, PHENotype SIMulator; SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2; Systems biology; TLR, Toll-like Receptor.