Aripiprazole as a Candidate Treatment of COVID-19 Identified Through Genomic Analysis

Benedicto Crespo-Facorro; Miguel Ruiz-Veguilla; Javier Vázquez-Bourgon; Ana C Sánchez-Hidalgo; Nathalia Garrido-Torres; Jose M Cisneros; Carlos Prieto; Jesus Sainz

doi:10.3389/fphar.2021.646701

Aripiprazole as a Candidate Treatment of COVID-19 Identified Through Genomic Analysis

Front Pharmacol. 2021 Mar 2:12:646701. doi: 10.3389/fphar.2021.646701. eCollection 2021.

Authors

Benedicto Crespo-Facorro^{1

2}, Miguel Ruiz-Veguilla^{1

2}, Javier Vázquez-Bourgon^{2

3

4}, Ana C Sánchez-Hidalgo^{2

5}, Nathalia Garrido-Torres¹, Jose M Cisneros^{6

7}, Carlos Prieto⁸, Jesus Sainz⁹

Affiliations

¹ Department of Psychiatry, School of Medicine, University Hospital Virgen del Rocio-IBIS, Sevilla, Spain.
² Spanish Network for Research in Mental Health (CIBERSAM), Sevilla, Spain.
³ Department of Psychiatry, University Hospital Marques de Valdecilla - Instituto de Investigacion Marques de Valdecilla (IDIVAL), Santander, Spain.
⁴ Department of Medicine and Psychiatry, School of Medicine, University of Cantabria, Santander, Spain.
⁵ Seville Biomedical Research Centre (IBiS), Sevilla, Spain.
⁶ Department of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocio, University of Seville, Salamanca, Spain.
⁷ Spanish Network for Research in Infectious Diseases (REIPI), Madrid, Spain.
⁸ Bioinformatics Service, Nucleus, University of Salamanca, Salamanca, Spain.
⁹ Spanish National Research Council (CSIC), Institute of Biomedicine and Biotechnology of Cantabria, Santander, Spain.

Abstract

Background: Antipsychotics modulate expression of inflammatory cytokines and inducible inflammatory enzymes. Elopiprazole (a phenylpiperazine antipsychotic drug in phase 1) has been characterized as a therapeutic drug to treat SARS-CoV-2 infection in a repurposing study. We aim to investigate the potential effects of aripiprazole (an FDA approved phenylpiperazine) on COVID-19-related immunological parameters. Methods: Differential gene expression profiles of non-COVID-19 vs. COVID-19 RNA-Seq samples (CRA002390 project in GSA database) and drug-naïve patients with non-affective psychosis at baseline and after three months of aripiprazole treatment were identified. An integrative transcriptomic analyses of aripiprazole effects on differentially expressed genes in COVID-19 patients was performed. Findings: 82 out the 377 genes (21.7%) with expression significantly altered by aripiprazole have also their expression altered in COVID-19 patients and in 93.9% of these genes their expression is reverted by aripiprazole. The number of common genes with expression altered in both analyses is significantly higher than expected (Fisher's Exact Test, two tail; p value = 3.2e-11). 11 KEGG pathways were significantly enriched with genes with altered expression both in COVID-19 patients and aripiprazole medicated non-affective psychosis patients (p adj<0.05). The most significant pathways were associated to immune responses and mechanisms of hyperinflammation-driven pathology (i.e.,"inflammatory bowel disease (IBD)" (the most significant pathway with a p adj of 0.00021), "Th1 and Th2 cell differentiation" and "B cell receptor signaling pathway") that have been also associated with COVID19 clinical outcome. Interpretation: This exploratory investigation may provide further support to the notion that a protective effect is exerted by aripiprazole (phenylpiperazine) by modulating the expression of genes that have shown to be altered in COVID-19 patients. Along with many ongoing studies and clinical trials, repurposing available medications could be of use in countering SARS-CoV-2 infection, but require further studies and trials.

Keywords: SARS-CoV-2; coronavirus; elopiprazole; immunology; inflammation; psychosis; repurposing drugs.