Rapid repurposing of drugs for COVID-19

Guy, R. Kiplin; DiPaola, Robert S.; Romanelli, Frank; Dutch, Rebecca Ellis

doi:10.1126/science.abb9332

Cited by 290 publications

(269 citation statements)

References 16 publications

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“…Combined with the current ndings, several approved or experimental drugs have been repurposed against SARS-CoV-2 including remdesivir (HIV reverse transcriptase inhibitor), anti-in uenza favipiravir (RdRp inhibitor), ribavirin (RNA synthesis and capping inhibitor), anti-in uenza baloxavir marboxil (capdependent endonuclease), HIV protease inhibitors lopinavir and ritonavir, endocytosis inhibitor antimalarial chloroquine/hydroxychloroquine, antibiotic azithromycin, immunosuppressant cyclosporine (cyclophilin inhibitor), rapamycin (FKBP/mTORC inhibitor), tocilizumab (IL6 receptor antagonist), sarilumab (tocilizumab e cacy dependent), antihelminthic ivermectin (integrase and importin α/β1 inhibitor), antiprotozoal/antiviral netazoxanide (inhibitor of viral replication by tizoxanide metabolite), nefamostat/camostat (ACE2 receptor/TMPRSS2 inhibitor), antidepressant uvoxamine, INFβ-1a inhibitor (CD73 ecto-5 / -neucleotidase) are under clinical trials for COVID-19 treatment (Guy et al, 2020;Li et al, 2020;Bellingan et al, 2014;Caly et al, 2020;Grein et al, 2020;Wu et al, 2020;Uno, 2020).…”

Section: Resultsmentioning

confidence: 99%

“…The PDI network was constructed with STITCH: protein/compound query for the three groups A, B, and C comprising top 44 COVID-19 related genes, 255 DEGs among COVID-19 case compared to uninfected control, and 363 DEGs among ACE2 induced cell line treated with and without SARS-CoV-2, using STRING App of the Cytoscape software, version 3.7.2 (https://cytoscape.org/), according to Shannon et al (2003); the approved and experimental repurposable drugs against COVID-19 were included to create the PDI network (Guy et al, 2020;Li et al, 2020).…”

Section: Sars-cov-2 Protein and Drug Interaction (Pdi) Network Analysismentioning

confidence: 99%

“…Host-virus gene interaction in COVID-19 case and SARS-CoV-2 infected cell line. The RBD of FURIN preactivated SARS-CoV-2 spike protein binds with human ACE2 receptor in association with TMPRSS2 to facilitate viral entry by endocytosis (Guy et al, 2020). Following entry, the virus release genome into the cytosol by autophogosome-lysosomal pathway involving ULK, PI3K, ATG5-ATG12-ATG, and LC3-PE genes.…”

Section: Figures Figurementioning

confidence: 99%

“…Following entry, the virus release genome into the cytosol by autophogosome-lysosomal pathway involving ULK, PI3K, ATG5-ATG12-ATG, and LC3-PE genes. The genomic RNA containing ORF1a and ORF1b is translated to pp1a and pp1ab replicase polyproteins that auto-cleave into 16 nsps, to constitute the RTC, which synthesizes minus-stranded RNA (Gordon et al, 2020;Guy et al, 2020). Both full-length and subgenome-length minus strands are synthesized.…”

Section: Figures Figurementioning

confidence: 99%

“…As of June 25, 2020, the ongoing COVID-19 (coronavirus disease-2019) pandemic caused 9,296,202 people infections globally including 479,133 deaths (WHO, 2020), because of the lack of speci c treatments or vaccines. Repurposing drugs may possibly curtail the time and costs compared to de novo drug discovery, in addition to providing principal information on pharmacology and toxicology, as well as ascertaining novel indications for prompt clinical trials and regulatory assessment (Shaha et al, 2020;Gordon et al, 2020;Guy et al, 2020). The present study address this by mapping the interaction between viral proteins and human proteins in SARS-CoV-2 infected case compared to healthy control, in SARS-CoV-2 infected-compared to uninfected cell culture.…”

Section: Introductionmentioning

confidence: 97%

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Bioinformatic approaches towards identification of potential repurposable drugs for COVID-19

Mandal

2020

Preprint

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Abstract Repurposing existing drugs approved for other conditions is crucial to identifying specific therapeutics against SARS-CoV-2 causing COVID-19 (coronavirus disease-2019) pandemic. Towards this attempt, it is important to understand how this virus hijacks the host system during the course of infection and determine potential virus- and host-targeted inhibitors. This study elucidates the underlying virus-host interaction based on differentially expressed gene profiling, functional enrichment and pathway analysis, protein-protein and protein-drug interactions utilizing the information on transcriptional response to SARS-CoV-2 infection from GSE 147507 dataset containing COVID-19 case relative to healthy control and infected cell culture compared to uninfected one. Low IFN signaling, chemokines level elevation, and proinflammatory cytokines release were observed markedly. We identified MYC-rapamycin and ABCG2-rapamycin interactions, and unique gene signatures in case (regulation of protein modification and MAPK signaling) as well as in cell (metabolic dysregulation and interferon signaling) different from known COVID-19 genes.

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Section: Resultsmentioning

confidence: 99%

Section: Sars-cov-2 Protein and Drug Interaction (Pdi) Network Analysismentioning

confidence: 99%

Section: Figures Figurementioning

confidence: 99%

Section: Figures Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Bioinformatic approaches towards identification of potential repurposable drugs for COVID-19

Mandal

2020

Preprint

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Effect of Fluvoxamine vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19

McCarthy

Naggie

Boulware

et al. 2023

JAMA

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ImportanceThe effectiveness of fluvoxamine to shorten symptom duration or prevent hospitalization among outpatients with mild to moderate symptomatic COVID-19 is unclear.ObjectiveTo evaluate the efficacy of low-dose fluvoxamine (50 mg twice daily) for 10 days compared with placebo for the treatment of mild to moderate COVID-19 in the US.Design, Setting, and ParticipantsThe ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-6) platform randomized clinical trial was designed to test repurposed medications in outpatients with mild to moderate COVID-19. A total of 1288 participants aged 30 years or older with test-confirmed SARS-CoV-2 infection and experiencing 2 or more symptoms of acute COVID-19 for 7 days or less were enrolled between August 6, 2021, and May 27, 2022, at 91 sites in the US.InterventionsParticipants were randomized to receive 50 mg of fluvoxamine twice daily for 10 days or placebo.Main Outcomes and MeasuresThe primary outcome was time to sustained recovery (defined as the third day of 3 consecutive days without symptoms). There were 7 secondary outcomes, including a composite outcome of hospitalization, urgent care visit, emergency department visit, or death through day 28.ResultsAmong 1331 participants who were randomized (median age, 47 years [IQR, 38-57 years]; 57% were women; and 67% reported receiving ≥2 doses of a SARS-CoV-2 vaccine), 1288 completed the trial (674 in the fluvoxamine group and 614 in the placebo group). The median time to sustained recovery was 12 days (IQR, 11-14 days) in the fluvoxamine group and 13 days (IQR, 12-13 days) in the placebo group (hazard ratio [HR], 0.96 [95% credible interval, 0.86-1.06], posterior P = .21 for the probability of benefit [determined by an HR &gt;1]). For the composite outcome, 26 participants (3.9%) in the fluvoxamine group were hospitalized, had an urgent care visit, had an emergency department visit, or died compared with 23 participants (3.8%) in the placebo group (HR, 1.1 [95% credible interval, 0.5-1.8], posterior P = .35 for the probability of benefit [determined by an HR &lt;1]). One participant in the fluvoxamine group and 2 participants in the placebo group were hospitalized; no deaths occurred in either group. Adverse events were uncommon in both groups.Conclusions and RelevanceAmong outpatients with mild to moderate COVID-19, treatment with 50 mg of fluvoxamine twice daily for 10 days, compared with placebo, did not improve time to sustained recovery. These findings do not support the use of fluvoxamine at this dose and duration in patients with mild to moderate COVID-19.Trial RegistrationClinicalTrials.gov Identifier: NCT04885530

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Confronting theCOVID‐19 Pandemic: December 2019–May 2020

Dolle

Abraham

Norman³

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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The SARS‐CoV‐2 (COVID‐19) pandemic was officially declared by the World Health Organization on 11 March, 2020. From the initial public reports from China in December 2019, the contagion blazed its way from ground zero in Wuhan, China into 165 countries. The health disaster caught the planet by surprise. At the time of this writing, 6.6 million COVID‐19 cases were confirmed worldwide. Central and South America are the latest hotspots. Utilizing state‐of‐the‐art science and technology, industry, government, and academic enterprises internationally are engaged in a monumental campaign to combat and eliminate the viral threat. Small‐molecule therapeutics discovery largely by way of drug repurposing and accelerated vaccine development are at the forefront of this campaign. Within five months time, 500 unique therapeutic agents have advanced into development, >150 clinical trials initiated, and seven agents authorized for emergency use. This article presents a snapshot of these activities as of 29 May 2020.

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Rapid repurposing of drugs for COVID-19

Abstract: The emergence of a new coronaviral respiratory disease calls for repurposing existing drugs

Cited by 290 publications

References 16 publications

Bioinformatic approaches towards identification of potential repurposable drugs for COVID-19

Bioinformatic approaches towards identification of potential repurposable drugs for COVID-19

Effect of Fluvoxamine vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19

Confronting theCOVID‐19 Pandemic: December 2019–May 2020

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