scholarly journals Identification of SARS-CoV-2–induced pathways reveals drug repurposing strategies

2021 ◽  
Vol 7 (27) ◽  
pp. eabh3032
Author(s):  
Namshik Han ◽  
Woochang Hwang ◽  
Konstantinos Tzelepis ◽  
Patrick Schmerer ◽  
Eliza Yankova ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Viral Replication ◽  
Rapid Development ◽  
Drug Repurposing ◽  
Mechanisms Of Action ◽  
Neural Network Analysis ◽  
Cell Assays ◽  
Artificial Neural Network Analysis ◽  
Approved Drugs ◽  
Disease Signatures

The global outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates the rapid development of new therapies against coronavirus disease 2019 (COVID-19) infection. Here, we present the identification of 200 approved drugs, appropriate for repurposing against COVID-19. We constructed a SARS-CoV-2–induced protein network, based on disease signatures defined by COVID-19 multiomics datasets, and cross-examined these pathways against approved drugs. This analysis identified 200 drugs predicted to target SARS-CoV-2–induced pathways, 40 of which are already in COVID-19 clinical trials, testifying to the validity of the approach. Using artificial neural network analysis, we classified these 200 drugs into nine distinct pathways, within two overarching mechanisms of action (MoAs): viral replication (126) and immune response (74). Two drugs (proguanil and sulfasalazine) implicated in viral replication were shown to inhibit replication in cell assays. This unbiased and validated analysis opens new avenues for the rapid repurposing of approved drugs into clinical trials.

scholarly journals Identification of SARS-CoV-2 induced pathways reveal drug repurposing strategies

2020 ◽  
Author(s):  
Namshik Han ◽  
Woochang Hwang ◽  
Konstantinos Tzelepis ◽  
Patrick Schmerer ◽  
Eliza Yankova ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Viral Replication ◽  
Rapid Development ◽  
Drug Repurposing ◽  
Mechanisms Of Action ◽  
Neural Network Analysis ◽  
Cellular Assays ◽  
Artificial Neural Network Analysis ◽  
Approved Drugs ◽  
Disease Signatures

SUMMARYThe global outbreak of SARS-CoV-2 necessitates the rapid development of new therapies against COVID-19 infection. Here, we present the identification of 200 approved drugs, appropriate for repurposing against COVID-19. We constructed a SARS-CoV-2-induced protein (SIP) network, based on disease signatures defined by COVID-19 multi-omic datasets(Bojkova et al., 2020; Gordon et al., 2020), and cross-examined these pathways against approved drugs. This analysis identified 200 drugs predicted to target SARS-CoV-2-induced pathways, 40 of which are already in COVID-19 clinical trials(Clinicaltrials.gov, 2020) testifying to the validity of the approach. Using artificial neural network analysis we classified these 200 drugs into 9 distinct pathways, within two overarching mechanisms of action (MoAs): viral replication (130) and immune response (70). A subset of drugs implicated in viral replication were tested in cellular assays and two (proguanil and sulfasalazine) were shown to inhibit replication. This unbiased and validated analysis opens new avenues for the rapid repurposing of approved drugs into clinical trials.

scholarly journals Mining of high throughput screening database reveals AP-1 and autophagy pathways as potential targets for COVID-19 therapeutics

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hu Zhu ◽  
Catherine Z. Chen ◽  
Srilatha Sakamuru ◽  
Jinghua Zhao ◽  
Deborah K. Ngan ◽  
...  
Keyword(s):  
Clinical Trials ◽  
High Throughput Screening ◽  
Animal Studies ◽  
Cytopathic Effect ◽  
Mechanisms Of Action ◽  
Activity Profile ◽  
Pathway Activity ◽  
Global Pandemic ◽  
Approved Drugs

AbstractThe recent global pandemic of the Coronavirus disease 2019 (COVID-19) caused by the new coronavirus SARS-CoV-2 presents an urgent need for the development of new therapeutic candidates. Many efforts have been devoted to screening existing drug libraries with the hope to repurpose approved drugs as potential treatments for COVID-19. However, the antiviral mechanisms of action of the drugs found active in these phenotypic screens remain largely unknown. In an effort to deconvolute the viral targets in pursuit of more effective anti-COVID-19 drug development, we mined our in-house database of approved drug screens against 994 assays and compared their activity profiles with the drug activity profile in a cytopathic effect (CPE) assay of SARS-CoV-2. We found that the autophagy and AP-1 signaling pathway activity profiles are significantly correlated with the anti-SARS-CoV-2 activity profile. In addition, a class of neurology/psychiatry drugs was found to be significantly enriched with anti-SARS-CoV-2 activity. Taken together, these results provide new insights into SARS-CoV-2 infection and potential targets for COVID-19 therapeutics, which can be further validated by in vivo animal studies and human clinical trials.

scholarly journals Repurposing of Antimicrobial Agents for Cancer Therapy: What Do We Know?

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3193
Author(s):  
Christina Pfab ◽  
Luisa Schnobrich ◽  
Samir Eldnasoury ◽  
André Gessner ◽  
Nahed El-Najjar
Keyword(s):  
Clinical Trials ◽  
Antimicrobial Agents ◽  
Large Body ◽  
Drug Repurposing ◽  
Extensive Discussion ◽  
Attrition Rates ◽  
Beneficial Effects ◽  
Stage Of Development ◽  
Development Costs ◽  
Approved Drugs

The substantial costs of clinical trials, the lengthy timelines of new drug discovery and development, along the high attrition rates underscore the need for alternative strategies for finding quickly suitable therapeutics agents. Given that most approved drugs possess more than one target tightly linked to other diseases, it encourages promptly testing these drugs in patients. Over the past decades, this has led to considerable attention for drug repurposing, which relies on identifying new uses for approved or investigational drugs outside the scope of the original medical indication. The known safety of approved drugs minimizes the possibility of failure for adverse toxicology, making them attractive de-risked compounds for new applications with potentially lower overall development costs and shorter development timelines. This latter case is an exciting opportunity, specifically in oncology, due to increased resistance towards the current therapies. Indeed, a large body of evidence shows that a wealth of non-cancer drugs has beneficial effects against cancer. Interestingly, 335 drugs are currently being evaluated in different clinical trials for their potential activities against various cancers (Redo database). This review aims to provide an extensive discussion about the anti-cancer activities exerted by antimicrobial agents and presents information about their mechanism(s) of action and stage of development/evaluation.

scholarly journals Repurposing inhibitors for SARS-CoV2 main protease

2020 ◽  
Author(s):  
Kumar Sharp
Keyword(s):  
Viral Replication ◽  
Active Sites ◽  
Drug Repurposing ◽  
Chemotherapeutic Drugs ◽  
Short Term ◽  
Main Protease ◽  
Potential Binding ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract SARS-CoV2 main protease is important for viral replication and one of the most potential targets for drug development in this current pandemic. Drug repurposing is a promising field to provide potential short-term acceptable therapy for management of coronavirus till a specific anti-viral for coronavirus is developed. In-silico drug repurposing screening is the current fastest way to repurpose drugs by targeting active sites in fraction of seconds. In this study, SARS-CoV2 main protease is being targeted by 1050 FDA-approved drugs to inhibit its activity thereby interfering with viral replication. Chemotherapeutic drugs and anti-retroviral drugs have shown potential binding as inhibitor. In-vitro and clinical trials required to establish final fact.

Classification of Coronavirus (COVID-19) Treatments and Drugs Based on Mechanism of Action, Efficacy, and Safety

2020 ◽  
Vol 9 (2) ◽  
Author(s):  
Mahi Ravi ◽  
William Jackson
Keyword(s):  
Mechanism Of Action ◽  
Death Rate ◽  
Rapid Development ◽  
Mechanisms Of Action ◽  
Efficacy And Safety ◽  
Novel Drugs ◽  
The Us ◽  
Approved Drugs ◽  
Fda Approved Drugs

The recently discovered coronavirus SARS-CoV-2 has forced countries into lockdown, people into quarantines, and economies to a standstill. Currently there are no FDA approved treatments for COVID-19, the disease caused by this new coronavirus strain. With over 2.8 million cases in the US as of July 3 and a death rate of approximately 5.9%, an effective treatment is urgently needed (Center for Disease Control [CDC], 2020). To date there are few comprehensive reviews of therapeutic options for COVID-19. Here we present the general types and mechanisms of action for drugs currently available or in rapid development. This paper highlights FDA approved drugs that can be repurposed and therefore used immediately to test for coronavirus efficacy as well as novel drugs and vaccines specifically targeted to COVID-19 vulnerabilities.

scholarly journals Broad anti-coronaviral activity of FDA approved drugs against SARS-CoV-2 in vitro and SARS-CoV in vivo

2020 ◽  
Author(s):  
Stuart Weston ◽  
Christopher M. Coleman ◽  
Rob Haupt ◽  
James Logue ◽  
Krystal Matthews ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Rapid Development ◽  
Drug Repurposing ◽  
Ic50 Values ◽  
Human Use ◽  
Approved Drugs ◽  
Fda Approved Drugs

AbstractSARS-CoV-2 emerged in China at the end of 2019 and has rapidly become a pandemic with roughly 2.7 million recorded COVID-19 cases and greater than 189,000 recorded deaths by April 23rd, 2020 (www.WHO.org). There are no FDA approved antivirals or vaccines for any coronavirus, including SARS-CoV-2. Current treatments for COVID-19 are limited to supportive therapies and off-label use of FDA approved drugs. Rapid development and human testing of potential antivirals is greatly needed. A quick way to test compounds with potential antiviral activity is through drug repurposing. Numerous drugs are already approved for human use and subsequently there is a good understanding of their safety profiles and potential side effects, making them easier to fast-track to clinical studies in COVID-19 patients. Here, we present data on the antiviral activity of 20 FDA approved drugs against SARS-CoV-2 that also inhibit SARS-CoV and MERS-CoV. We found that 17 of these inhibit SARS-CoV-2 at a range of IC50 values at non-cytotoxic concentrations. We directly follow up with seven of these to demonstrate all are capable of inhibiting infectious SARS-CoV-2 production. Moreover, we have evaluated two of these, chloroquine and chlorpromazine, in vivo using a mouse-adapted SARS-CoV model and found both drugs protect mice from clinical disease.

scholarly journals An Update on Antiviral Therapy Against SARS-CoV-2: How Far Have We Come?

2021 ◽  
Vol 12 ◽  
Author(s):  
Omkar Indari ◽  
Shweta Jakhmola ◽  
Elangovan Manivannan ◽  
Hem Chandra Jha
Keyword(s):  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Drug Repurposing ◽  
Clinical Findings ◽  
Open Label ◽  
Plasma Therapy ◽  
Clinical Safety ◽  
Treatment Research ◽  
Repurposed Drugs ◽  
Approved Drugs

COVID-19 pandemic has spread worldwide at an exponential rate affecting millions of people instantaneously. Currently, various drugs are under investigation to treat an enormously increasing number of COVID-19 patients. This dreadful situation clearly demands an efficient strategy to quickly identify drugs for the successful treatment of COVID-19. Hence, drug repurposing is an effective approach for the rapid discovery of frontline arsenals to fight against COVID-19. Successful application of this approach has resulted in the repurposing of some clinically approved drugs as potential anti-SARS-CoV-2 candidates. Several of these drugs are either antimalarials, antivirals, antibiotics or corticosteroids and they have been repurposed based on their potential to negate virus or reduce lung inflammation. Large numbers of clinical trials have been registered to evaluate the effectiveness and clinical safety of these drugs. Till date, a few clinical studies are complete and the results are primary. WHO also conducted an international, multi-country, open-label, randomized trials-a solidarity trial for four antiviral drugs. However, solidarity trials have few limitations like no placebos were used, additionally any drug may show effectiveness for a particular population in a region which may get neglected in solidarity trial analysis. The ongoing randomized clinical trials can provide reliable long-term follow-up results that will establish both clinical safety and clinical efficacy of these drugs with respect to different regions, populations and may aid up to worldwide COVID-19 treatment research. This review presents a comprehensive update on majorly repurposed drugs namely chloroquine, hydroxychloroquine, remdesivir, lopinavir-ritonavir, favipiravir, ribavirin, azithromycin, umifenovir, oseltamivir as well as convalescent plasma therapy used against SARS-CoV-2. The review also summarizes the data recorded on the mechanism of anti-SARS-CoV-2 activity of these repurposed drugs along with the preclinical and clinical findings, therapeutic regimens, pharmacokinetics, and drug-drug interactions.

scholarly journals In silico Drug Repurposing for COVID-19: Targeting SARS-CoV-2 Proteins through Docking and Quantum Mechanical Scoring

2020 ◽  
Author(s):  
Claudio Cavasotto ◽  
Juan Di Filippo
Keyword(s):  
Clinical Trials ◽  
Antiviral Drug ◽  
Drug Repurposing ◽  
Rational Drug Design ◽  
World Health ◽  
Quantum Mechanical ◽  
S Protein ◽  
Compound Screening ◽  
Health Organization ◽  
Approved Drugs

In December 2019, an infectious disease caused by the coronavirus SARS-CoV-2 appeared in Wuhan, China. This disease (COVID-19) spread rapidly worldwide, and on March 2020 was declared a pandemic by the World Health Organization (WHO). Today, almost 1,5 million people have been infected, with more than 85,000 casualties. Today, no vaccine nor antiviral drug is available. While the development of a vaccine might take at least a year, and for a novel drug, even longer; finding a new use to an old drug (drug repurposing) could be the most effective strategy. We present a docking-based screening using a quantum mechanical scoring of a library built from approved drugs and compounds undergoing clinical trials, against three SARS-CoV-2 target proteins: the spike or S-protein, and two proteases, the main protease and the papain-like<br>protease. The S-protein binds directly to the Angiotensin Converting Enzyme 2 receptor of the human host cell surface, while the two proteases process viral polyproteins.<br>Following the anaylysis of our structure-based compound screening, we propose several structurally diverse compounds (either FDA-approved or in clinical trials) that could display antiviral activity against SARS-CoV-2. Clearly, these compounds should be further evaluated in experimental assays and clinical trials to confirm their actual activity against the disease. We hope that these findings may contribute to the rational drug design against COVID-19.

scholarly journals In silico Drug Repurposing for COVID-19: Targeting SARS-CoV-2 Proteins through Docking and Quantum Mechanical Scoring

2020 ◽  
Author(s):  
Claudio Cavasotto ◽  
Juan Di Filippo
Keyword(s):  
Clinical Trials ◽  
Antiviral Drug ◽  
Drug Repurposing ◽  
Rational Drug Design ◽  
World Health ◽  
Quantum Mechanical ◽  
Chemical Library ◽  
S Protein ◽  
Health Organization ◽  
Approved Drugs

In December 2019, an infectious disease caused by the coronavirus SARS-CoV-2 appeared in Wuhan, China. This disease (COVID-19) spread rapidly worldwide, and on March 2020 was declared a pandemic by the World Health Organization (WHO). Today, more than 4.7 million people have been infected, with almost 320,000 casualties, while no vaccine nor antiviral drug is in sight. The development of a vaccine might take at least a year, and even longer for a novel drug; thus, finding a new use to an old drug (drug repurposing) could be the most effective strategy. We present a high-throughput docking approach using a novel quantum mechanical scoring for screening a chemical library of ~11,500 molecules built from FDA-approved drugs and compounds undergoing clinical trials, against three SARS-CoV-2 target proteins: the spike or S-protein, and two proteases, the main protease and the papain-like protease. The S-protein binds directly to the Angiotensin Converting Enzyme 2 receptor of the human host cell surface, while the two proteases process viral polyproteins. Following the analysis of our structure-based virtual screening, we propose several structurally diverse compounds that could display antiviral activity against SARS-CoV-2. Clearly, these compounds should be further evaluated in experimental assays and clinical trials to confirm their actual activity against the disease. We hope that these findings may contribute to the rational drug design against COVID-19.

scholarly journals Data-Driven Drug Repurposing for COVID-19

2020 ◽  
Author(s):  
Raghvendra Mall ◽  
Abdurrahman Elbasir ◽  
Hossam Al Meer ◽  
Sanjay Chawla ◽  
Ehsan Ullah
Keyword(s):  
Clinical Trials ◽  
De Novo ◽  
Drug Repurposing ◽  
Binding Energies ◽  
Protein Activity ◽  
De Novo Drug Design ◽  
Docking Simulations ◽  
Antibiotic Drugs ◽  
Approved Drugs ◽  
Ranked List

<div>Motivation: A global effort is underway to identify drugs for the treatment of COVID-19. Since de novo drug design is an extremely long, time-consuming, and expensive process, efforts are underway to discover existing drugs that can be</div><div>repurposed for COVID-19.</div><div><br></div><div>Model: We propose a machine learning representation framework that uses deep learning induced vector embeddings of drugs and viral proteins as features to predict drug-viral protein activity. The prediction model in-turn is used to build an ensemble framework to rank approved drugs based on their ability to inhibit the three main proteases (enzymes) of the SARS-COV-2 virus.</div><div><br></div><div>Results: We identify a ranked list of 19 drugs as potential targets including 7 antivirals, 6 anticancer, 3 antibiotics, 2 antimalarial, and 1 antifungal. Several drugs, such as Remdesivir, Lopinavir, Ritonavir, and Hydroxychloroquine, in our ranked list, are currently in clinical trials. Moreover, through molecular docking simulations, we demonstrate that majority of the anticancer and antibiotic drugs in our ranked list have low binding energies and thus high binding affinity with the 3CL-pro protease of SARS-COV-2 virus.</div><div><br></div><div>Disclaimer: Our models are computational and the drugs suggested should not be taken for treating COVID-19 without a doctor's advice, as further wet-lab research and clinical trials are essential to elucidate their efficacy for this purpose.</div>

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