A genetically based computational drug repurposing framework for rapid identification of candidate compounds: application to COVID-19
et al., medRxiv, doi:10.1101/2025.01.10.25320348, Jan 2025
Vitamin A for COVID-19
48th treatment shown to reduce risk in
June 2023, now with p = 0.0052 from 15 studies.
No treatment is 100% effective. Protocols
combine treatments.
6,300+ studies for
210+ treatments. c19early.org
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Computational drug repurposing study integrating genetically regulated gene expression (GReX) and pharmaceutical databases to identify 7 FDA-approved compounds that may reverse COVID-19-related gene expression.
Analysis of 755,346 people in the Veterans Health Administration cohort showed that retinol and azathioprine were associated with reduced incidence of COVID-19.
In vitro analysis showed nelfinavir and saquinavir inhibited SARS-CoV-2 replication by ~95% and ~65% respectively.
11 preclinical studies support the efficacy of vitamin A for COVID-19:
Vitamin A has been identified by the European Food Safety Authority (EFSA) as having sufficient evidence for a causal relationship between intake and optimal immune system function11-13.
Vitamin A has potent antiviral activity against SARS-CoV-2 in both human cell lines and human organoids of the lower respiratory tract (active metabolite all-trans retinoic acid, ATRA)8, is predicted to bind critical host and viral proteins for SARS-CoV-2 and may compensate for gene expression changes related to SARS-CoV-22-4, may be beneficial for COVID-19 via antiviral, anti-inflammatory, and immunomodulatory effects according to network pharmacology analysis5, reduces barrier compromise caused by TNF-α in Calu-3 cells7, inhibits mouse coronavirus replication10, may stimulate innate immunity by activating interferon responses in an IRF3-dependent manner (ATRA)10, may reduce excessive inflammation induced by SARS-CoV-22, shows SARS-CoV-2 antiviral activity In Vitro2,6,9 , is effective against multiple SARS-CoV-2 variants in Calu-3 cells9, and inhibits the entry and replication of SARS-CoV-2 via binding to ACE2 / 3CLpro / RdRp / helicase / 3′-to-5′ exonuclease2.
Standard of Care (SOC) for COVID-19 in the study country,
the USA, is very poor with very low average efficacy for approved treatments14.
Only expensive, high-profit treatments were approved for early treatment. Low-cost treatments were excluded, reducing the probability of early treatment due to access and cost barriers, and eliminating complementary and synergistic benefits seen with many low-cost treatments.
|
risk of case, 19.0% lower, OR 0.81, p < 0.001, adjusted per study, multivariable, RR approximated with OR.
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| Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates |
1.
Voloudakis et al., A genetically based computational drug repurposing framework for rapid identification of candidate compounds: application to COVID-19, medRxiv, doi:10.1101/2025.01.10.25320348.
2.
Huang et al., All-trans retinoic acid acts as a dual-purpose inhibitor of SARS-CoV-2 infection and inflammation, Computers in Biology and Medicine, doi:10.1016/j.compbiomed.2024.107942.
3.
Chakraborty et al., In-silico screening and in-vitro assay show the antiviral effect of Indomethacin against SARS-CoV-2, Computers in Biology and Medicine, doi:10.1016/j.compbiomed.2022.105788.
4.
Pandya et al., Unravelling Vitamin B12 as a potential inhibitor against SARS-CoV-2: A computational approach, Informatics in Medicine Unlocked, doi:10.1016/j.imu.2022.100951.
5.
Li et al., Revealing the targets and mechanisms of vitamin A in the treatment of COVID-19, Aging, doi:10.18632/aging.103888.
6.
Moatasim et al., Potent Antiviral Activity of Vitamin B12 against Severe Acute Respiratory Syndrome Coronavirus 2, Middle East Respiratory Syndrome Coronavirus, and Human Coronavirus 229E, Microorganisms, doi:10.3390/microorganisms11112777.
7.
DiGuilio et al., The multiphasic TNF-α-induced compromise of Calu-3 airway epithelial barrier function, Experimental Lung Research, doi:10.1080/01902148.2023.2193637.
8.
Tong et al., A Retinol Derivative Inhibits SARS-CoV-2 Infection by Interrupting Spike-Mediated Cellular Entry, mBio, doi:10.1128/mbio.01485-22.
9.
Morita et al., All-Trans Retinoic Acid Exhibits Antiviral Effect against SARS-CoV-2 by Inhibiting 3CLpro Activity, Viruses, doi:10.3390/v13081669.
10.
Franco et al., Retinoic Acid-Mediated Inhibition of Mouse Coronavirus Replication Is Dependent on IRF3 and CaMKK, Viruses, doi:10.3390/v16010140.
11.
Galmés et al., Suboptimal Consumption of Relevant Immune System Micronutrients Is Associated with a Worse Impact of COVID-19 in Spanish Populations, Nutrients, doi:10.3390/nu14112254.
12.
Galmés (B) et al., Current State of Evidence: Influence of Nutritional and Nutrigenetic Factors on Immunity in the COVID-19 Pandemic Framework, Nutrients, doi:10.3390/nu12092738.
13.
EFSA, Scientific Opinion on the substantiation of health claims related to vitamin A and cell differentiation (ID 14), function of the immune system (ID 14), maintenance of skin and mucous membranes (ID 15, 17), maintenance of vision (ID 16), maintenance of bone (ID 13, 17), maintenance of teeth (ID 13, 17), maintenance of hair (ID 17), maintenance of nails (ID 17), metabolism of iron (ID 206), and protection of DNA, proteins and lipids from oxidative damage (ID 209) pursuant to Article 13(1) of Regulation (EC) No 1924/2006, EFSA Journal, doi:10.2903/j.efsa.2009.1221.
Voloudakis et al., 14 Jan 2025, retrospective, USA, preprint, 21 authors.
Contact: georgios.voloudakis@mssm.edu, panagiotis.roussos@mssm.edu.
A genetically based computational drug repurposing framework for rapid identification of candidate compounds: application to COVID-19
doi:10.1101/2025.01.10.25320348
Background The development and approval of novel drugs are typically time-intensive and expensive. Leveraging a computational drug repurposing framework that integrates disease-relevant genetically regulated gene expression (GReX) and large longitudinal electronic medical record (EMR) databases can expedite the repositioning of existing medications. However, validating computational predictions of the drug repurposing framework remains a challenge.
Methods To benchmark the drug repurposing framework, we first performed a 5-method-rank-based computational drug prioritization pipeline by integrating multi-tissue GReX associated with COVID-19-related hospitalization, with drug transcriptional signature libraries from the Library of Integrated Network-Based Cellular Signatures. We prioritized FDA-approved medications from the 10 top-ranked compounds, and assessed their association with COVID-19 incidence within the Veterans Health Administration (VHA) cohort (~9 million individuals). In parallel, we evaluated in vitro SARS-CoV-2 replication inhibition in human lung epithelial cells for the selected candidates.
Results Our in silico pipeline identified seven FDA-approved drugs among the top ten candidates. Six (imiquimod, nelfinavir and saquinavir, everolimus, azathioprine, and retinol) had sufficient prescribing rates or feasibility for further testing. In the VHA cohort, azathioprine (odds ratio [OR]=0.69, 95% CI 0.62-0.77) and retinol (OR=0.81, 95% CI 0.72-0.92) were significantly associated with reduced COVID-19 incidence. Conversely, nelfinavir and saquinavir demonstrated potent SARS-CoV-2 inhibition in vitro (~95% and ~65% viral load reduction, respectively). No single compound showed robust protection in both in vivo and in vitro settings. Conclusions These findings underscore the power of GReX-based drug repurposing in rapidly identifying existing therapies with potential clinical relevance; four out of six compounds showed a protective effect in one of the two validation approaches. Crucially, our results highlight how a complementary evaluation-combining epidemiological data and in vitro assays-helps refine
Abbreviations
Abbreviation Definition COVID-19 Coronavirus Disease 2019 SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2
Supplementary Information Additional File 1: Tables S1-11 Author information Contributions Conceptualization and study design: GV, JFF, JAL, PR. Data contribution or analysis tools: GV, KML, JMV, WZ, DH, SV, JB, MA, ZW, SR, LG, KC, JSL, SKI, S-WL, TLA, GEH, BRtO, JFF, JAL, PR. GV, KML, JMV, WZ, DH, SV, JB performed the analyses. GV, KML, JMV, JFF, JAL, PR wrote the manuscript with input from all authors.
Ethics declarations
Ethics approval and consent to participate Analysis of national VA data was conducted under the protocol, "Leveraging Electronic Health Information to Advance Precision Medicine (LEAP)", which was approved by VA Central Institutional Review Board and by the Research & Development Committees at Palo Alto, Salt Lake City, and West Haven VA Medical Centers.
Consent for publication
Not applicable
Competing interests The authors declare no competing interests.
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