Drug repurposing screens reveal FDA approved drugs active against SARS-Cov-2

Dittmar, Mark; Lee, Jae Seung; Whig, Kanupriya; Segrist, Elisha; Li, Minghua; Jurado, Kellie Ann; Samby, Kirandeep; Ramage, Holly; Schultz, D.; Cherry, Sara

doi:10.1101/2020.06.19.161042

Cited by 56 publications

(102 citation statements)

References 111 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Two groups performed genome-wide CRISPR-Cas9 screens to identify host factors required by SARS-CoV-2 (Heaton et al, 2020;Wei et al, 2020) with the hope that these screens would not only uncover the biology underlying this virus, but also identify druggable host factors that could be targeted to prevent virus spread or lessen disease. Other groups conducted drug repurposing screens using compound libraries enriched with FDA-approved or clinical phase drug candidates to identify off-theshelf interventions (Dittmar et al, 2020;Zhou et al, 2020). A complementary strategy to these screens is to nominate candidate host factors that are predicted to interact with viral proteins through immunoprecipitation mass spectrometry (IP-MS) of affinity tagged viral proteins.…”

Section: Introductionmentioning

confidence: 99%

Functional interrogation of a SARS-CoV-2 host protein interactome identifies unique and shared coronavirus host factors

Hoffmann

Schneider

Sánchez‐Rivera

et al. 2020

Preprint

View full text Add to dashboard Cite

SUMMARYThe ongoing SARS-CoV-2 pandemic has devastated the global economy and claimed nearly one million lives, presenting an urgent global health crisis. To identify host factors required for infection by SARS-CoV-2 and seasonal coronaviruses, we designed a focused high-coverage CRISPR-Cas9 library targeting 332 members of a recently published SARS-CoV-2 protein interactome. We leveraged the compact nature of this library to systematically screen four related coronaviruses (HCoV-229E, HCoV-NL63, HCoV-OC43 and SARS-CoV-2) at two physiologically relevant temperatures (33 °C and 37 °C), allowing us to probe this interactome at a much higher resolution relative to genome scale studies. This approach yielded several new insights, including unexpected virus and temperature specific differences in Rab GTPase requirements and GPI anchor biosynthesis, as well as identification of multiple pan-coronavirus factors involved in cholesterol homeostasis. This coronavirus essentiality catalog could inform ongoing drug development efforts aimed at intercepting and treating COVID-19, and help prepare for future coronavirus outbreaks.HIGHLIGHTSFocused CRISPR screens targeting host factors in the SARS-CoV-2 interactome were performed for SARS-CoV-2, HCoV-229E, HCoV-NL63, and HCoV-OC43 coronaviruses.Focused interactome CRISPR screens achieve higher resolution compared to genome-wide screens, leading to the identification of critical factors missed by the latter.Parallel CRISPR screens against multiple coronaviruses uncover host factors and pathways with pan-coronavirus and virus-specific functional roles.The number of host proteins that interact with a viral bait protein is not proportional to the number of functional interactors.Novel SARS-CoV-2 host factors are expressed in relevant cell types in the human airway.

show abstract

Section: Introductionmentioning

confidence: 99%

Functional interrogation of a SARS-CoV-2 host protein interactome identifies unique and shared coronavirus host factors

Hoffmann

Schneider

Sánchez‐Rivera

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…This choice was driven by the following: 1., favorable side-effect profile, 2 nd generation non-sedating in most individuals, 2., no major effect on normal physiology, since the indication is to alleviate allergy symptoms, 3., broad availability, wide use, low cost; 4., availability in a nasal formulation for potential effect on nasal colonization; 5., several H1 and H2 blockers identified in our screens and others, e.g. ebastine 8,28 ; and 6., positive clinical data with the H2 receptor antagonist famotidine. 21 Here we provide experimental proof that azelastine is effective against SARS-CoV-2 infection in the most widely employed in vitro assay system with Vero E6 cells with comparable EC50 value (~6 µM) determined for chloroquine, lopinavir, and remdesivir (7 to 11 µM) using the same cell line.…”

Section: Discussionmentioning

confidence: 60%

“…23 Several of the drugs predicted in this study have been shown to have activity against coronaviruses in vitro. Cepharanthine, a natural compound with anti-inflammatory and antineoplastic activities was identified in a recent large-scale high throughput COVID-19 drug repurposing project using libraries of ~3000 drugs (~1000 of these FDA approved drug) 8 and also by others. 24,25 Previous studies demonstrated its inhibitory effects on both SARS-CoV 26 and HCoV-OC43.…”

Section: Discussionmentioning

confidence: 99%

“…6 The discrepancy between the in vitro activity and the clinical efficacy of these drugs might be explained by recent data demonstrating the lack of potency against SARS-CoV-2 infection in respiratory epithelial cells. 7,8 Another rational approach, but truly drug repurposing cases are the angiotensin converting enzyme 2 (ACE2) inhibitors and angiotensin receptor antagonists widely used in anti-hypertensive therapy. Since ACE2 is the receptor for SARS-CoV-2 entry, but also shown to be protective against lung damage in animal models 9 , both beneficial and potential disease enhancing effects are considered.…”

Section: Introductionmentioning

confidence: 99%

“…12,13 This is also the basis of large-scale high throughput drug screening and computational prediction programs, both already applied to COVID-19 and several drugs have been recently identified with anti-SARS-CoV-2 activity in vitro. 8,14,15 Here we have applied a novel computational prediction approach relying on biochemical pathway-based strategy. Key to our strategy is the poly-pharmacological hypothesis, that drugs simultaneously interact and interfere with numerous targets and thereby rewire the biochemical pathway networks.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The Anti-histamine Azelastine, Identified by Computational Drug Repurposing, Inhibits SARS-CoV-2 Infection in Reconstituted Human Nasal Tissue In Vitro

Konrat¹,

Papp

Szijártó³

et al. 2020

Preprint

View full text Add to dashboard Cite

BackgroundThe COVID-19 pandemic is an enormous threat for healthcare systems and economies worldwide that urgently demands effective preventive and therapeutic strategies. Unlike the development of vaccines and new drugs specifically targeting SARS-CoV-2, repurposing of approved or clinically tested drugs can provide an immediate solution.MethodsWe applied a novel computational approach to search among approved and clinically tested drugs from the DrugBank database. Candidates were selected based on Shannon entropy homology and predefined activity profiles of three small molecules with proven anti-SARS-CoV activity and a published data set. Antiviral activity of a predicted drug, azelastine, was tested in vitro in SARS-CoV-2 infection assays with Vero E6 monkey kidney epithelial cells and reconstituted human nasal tissue. The effect on viral replication was assessed by quantification of viral genomes by droplet digital PCR.FindingsThe computational approach with four independent queries identified major drug families, most often and in overlapping fashion anti-infective, anti-inflammatory, anti-hypertensive, anti-histamine and neuroactive drugs. Azelastine, an histamine 1 receptor-blocker, was predicted in multiple screens, and based on its attractive safety profile and availability in nasal formulation, was selected for experimental testing. Azelastine significantly reduced cytopathic effect and SARS-CoV-2 infection of Vero E6 cells with an EC50 of ∼6 μM both in a preventive and treatment setting. Furthermore, azelastine in a commercially available nasal spray tested at 5-fold dilution was highly potent in inhibiting viral propagation in SARS-CoV-2 infected reconstituted human nasal tissue.InterpretationsAzelastine, an anti-histamine, available in nasal sprays developed against allergic rhinitis may be considered as a topical prevention or treatment of nasal colonization with SARS-CoV-2. As such, it could be useful in reducing viral spread and prophylaxis of COVID-19. Ultimately, its potential benefit should be proven in clinical studies.Fundingprovided by the Hungarian government to the National Laboratory of Virology and by CEBINA GmbH.

show abstract

Drug repurposing for viral cancers: A paradigm of machine learning, deep learning, and virtual screening‐based approaches

Ahmed

Kang

Kim

et al. 2023

Journal of Medical Virology

View full text Add to dashboard Cite

Cancer management is major concern of health organizations and viral cancers account for approximately 15.4% of all known human cancers. Due to large number of patients, efficient treatments for viral cancers are needed. De novo drug discovery is time consuming and expensive process with high failure rate in clinical stages. To address this problem and provide treatments to patients suffering from viral cancers faster, drug repurposing emerges as an effective alternative which aims to find the other indications of the Food and Drug Administration approved drugs. Applied to viral cancers, drug repurposing studies following the niche have tried to find if already existing drugs could be used to treat viral cancers. Multiple drug repurposing approaches till date have been introduced with successful results in viral cancers and many drugs have been successfully repurposed various viral cancers.Here in this study, a critical review of viral cancer related databases, tools, and different machine learning, deep learning and virtual screening-based drug repurposing studies focusing on viral cancers is provided. Additionally, the mechanism of viral cancers is presented along with drug repurposing case study specific to each viral cancer. Finally, the limitations and challenges of various approaches along with possible solutions are provided.antihepatitis B virus antivirals, antiviral agents, artificial intelligence, drug repurposing, rational drug design | INTRODUCTIONDrug repurposing (also referred to as drug repositioning, drug reprofiling, drug redirecting, drug rescue and more 1 ) is a method for finding new indications beyond the scope of original indications of already approved drugs. 2 A conventional method of drug discovery is quite time taking and expensive task. Time required for a de novo drug is 12-17 years with an estimated expense of $2-$3 billion whereas the success rate is less than 10%. 3 This renders de novo drug discovery a risky process. Drug repurposing is an effective alternative to de novo drug discovery and offers many benefits such as reducing the time and money required to 5-7 years 4,5 and $200-$300 million, respectively, since much of the toxicity and efficacy information is already known. It also increases the success rate in clinical development and testing phases. 6 Success stories of drug repurposing have resulted in serendipity and by physicians' observation. 7 One such example is

show abstract

Drug repurposing screens reveal FDA approved drugs active against SARS-Cov-2

Cited by 56 publications

References 111 publications

Functional interrogation of a SARS-CoV-2 host protein interactome identifies unique and shared coronavirus host factors

Functional interrogation of a SARS-CoV-2 host protein interactome identifies unique and shared coronavirus host factors

The Anti-histamine Azelastine, Identified by Computational Drug Repurposing, Inhibits SARS-CoV-2 Infection in Reconstituted Human Nasal Tissue In Vitro

Drug repurposing for viral cancers: A paradigm of machine learning, deep learning, and virtual screening‐based approaches

Contact Info

Product

Resources

About