scholarly journals In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication

2020 ◽  
Author(s):  
Franck Touret ◽  
Magali Gilles ◽  
Karine Barral ◽  
Antoine Nougairède ◽  
Etienne Decroly ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Chemical Composition ◽  
In Vitro Screening ◽  
Short Term ◽  
Chemical Library ◽  
New Information ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Potential Inhibitors

SummaryA novel coronavirus, named SARS-CoV-2, emerged in 2019 from Hubei region in China and rapidly spread worldwide. As no approved therapeutics exists to treat Covid-19, the disease associated to SARS-Cov-2, there is an urgent need to propose molecules that could quickly enter into clinics. Repurposing of approved drugs is a strategy that can bypass the time consuming stages of drug development. In this study, we screened the Prestwick Chemical Library® composed of 1,520 approved drugs in an infected cell-based assay. 90 compounds were identified. The robustness of the screen was assessed by the identification of drugs, such as Chloroquine derivatives and protease inhibitors, already in clinical trials. The hits were sorted according to their chemical composition and their known therapeutic effect, then EC50 and CC50 were determined for a subset of compounds. Several drugs, such as Azithromycine, Opipramol, Quinidine or Omeprazol present antiviral potency with 2<EC50<20µM. By providing new information on molecules inhibiting SARS-CoV-2 replication in vitro, this study could contribute to the short-term repurposing of drugs against Covid-19.

scholarly journals In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Franck Touret ◽  
Magali Gilles ◽  
Karine Barral ◽  
Antoine Nougairède ◽  
Jacques van Helden ◽  
...  
Keyword(s):  
Antiviral Effect ◽  
Antiarrhythmic Agents ◽  
Chemical Library ◽  
New Information ◽  
Cns Drugs ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Potential Inhibitors

Abstract A novel coronavirus, named SARS-CoV-2, emerged in 2019 in China and rapidly spread worldwide. As no approved therapeutics exists to treat COVID-19, the disease associated to SARS-Cov-2, there is an urgent need to propose molecules that could quickly enter into clinics. Repurposing of approved drugs is a strategy that can bypass the time-consuming stages of drug development. In this study, we screened the PRESTWICK CHEMICAL LIBRARY composed of 1,520 approved drugs in an infected cell-based assay. The robustness of the screen was assessed by the identification of drugs that already demonstrated in vitro antiviral effect against SARS-CoV-2. Thereby, 90 compounds were identified as positive hits from the screen and were grouped according to their chemical composition and their known therapeutic effect. Then EC50 and CC50 were determined for a subset of 15 compounds from a panel of 23 selected drugs covering the different groups. Eleven compounds such as macrolides antibiotics, proton pump inhibitors, antiarrhythmic agents or CNS drugs emerged showing antiviral potency with 2 < EC50 ≤ 20 µM. By providing new information on molecules inhibiting SARS-CoV-2 replication in vitro, this study provides information for the selection of drugs to be further validated in vivo. Disclaimer: This study corresponds to the early stages of antiviral development and the results do not support by themselves the use of the selected drugs to treat SARS-CoV-2 infection.

scholarly journals Virtual Screening of Potential Inhibitors for SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Carlos Javier Alméciga-Díaz ◽  
Luisa N. Pimentel-Vera ◽  
Angela Caro ◽  
Angela Mosquera ◽  
Camilo Andrés Castellanos Moreno ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Clinical Information ◽  
Virus Genome ◽  
Pharmacological Agents ◽  
Main Protease ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Potential Inhibitors

Coronavirus Disease 2019 (Covid-19) was first described in December 2019 in Wuhan, Hubei Province, China; and produced by a novel coronavirus designed as the acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Covid-19 has become a pandemic reaching over 1.3 million confirmed cases and 73,000 deaths. Several efforts have been done to identify pharmacological agents that can be used to treat patients and protect healthcare professionals. The sequencing of the virus genome not only has offered the possibility to develop a vaccine, but also to identified and characterize the virus proteins. Among these proteins, main protease (Mpro) has been identified as a potential therapeutic target, since it is essential for the processing other viral proteins. Crystal structures of SARS-CoV-2 Mpro and inhibitors has been described during the last months. To describe additional compounds that can inhibit SARS-CoV-2 Mpro, in this study we performed a molecular docking-based virtual screening against a library of experimental and approved drugs. Top 10 hits included Pictilisib, Nimorazole, Ergoloid mesylates, Lumacaftor, Cefuroxime, Cepharanhine, and Nilotinib. These compounds were predicted to have higher binding affinity for SARS-CoV-2 Mpro than previously reported inhibitors for this protein, suggesting a higher potential to inhibit virus replication. Since the identified drugs have both pre-clinical and clinical information, we consider that these results may contribute to the identification of treatment alternative for Covid-19. Nevertheless, in vitro and in vivo confirmation should be performed before these compounds could be translated to the clinic.

scholarly journals A Phenylfurocoumarin Derivative Reverses ABCG2-Mediated Multidrug Resistance In Vitro and In Vivo

2021 ◽  
Vol 22 (22) ◽  
pp. 12502
Author(s):  
Shoji Kokubo ◽  
Shinobu Ohnuma ◽  
Megumi Murakami ◽  
Haruhisa Kikuchi ◽  
Shota Funayama ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Cells ◽  
High Throughput Screening ◽  
Atp Hydrolysis ◽  
Pheophorbide A ◽  
Chemical Library ◽  
Hct 116 ◽  
Potential Inhibitors

The ATP-binding cassette subfamily G member 2 (ABCG2) transporter is involved in the development of multidrug resistance in cancer patients. Many inhibitors of ABCG2 have been reported to enhance the chemosensitivity of cancer cells. However, none of these inhibitors are being used clinically. The aim of this study was to identify novel ABCG2 inhibitors by high-throughput screening of a chemical library. Among the 5812 compounds in the library, 23 compounds were selected in the first screening, using a fluorescent plate reader-based pheophorbide a (PhA) efflux assay. Thereafter, to validate these compounds, a flow cytometry-based PhA efflux assay was performed and 16 compounds were identified as potential inhibitors. A cytotoxic assay was then performed to assess the effect these 16 compounds had on ABCG2-mediated chemosensitivity. We found that the phenylfurocoumarin derivative (R)-9-(3,4-dimethoxyphenyl)-4-((3,3-dimethyloxiran-2-yl)methoxy)-7H-furo [3,2-g]chromen-7-one (PFC) significantly decreased the IC50 of SN-38 in HCT-116/BCRP colon cancer cells. In addition, PFC stimulated ABCG2-mediated ATP hydrolysis, suggesting that this compound interacts with the substrate-binding site of ABCG2. Furthermore, PFC reversed the resistance to irinotecan without causing toxicity in the ABCG2-overexpressing HCT-116/BCRP cell xenograft mouse model. In conclusion, PFC is a novel inhibitor of ABCG2 and has promise as a therapeutic to overcome ABCG2-mediated MDR, to improve the efficiency of cancer chemotherapy.

scholarly journals POTENTIAL THERAPIES FOR TREATMENT OF COVID-19

2020 ◽  
Vol 7 (1) ◽  
pp. 062-071
Author(s):  
Beatriz Gasser ◽  
Ricardo Andres Ramirez Uscategui
Keyword(s):  
Clinical Trials ◽  
Distress Syndrome ◽  
Multiple Organ ◽  
The Novel ◽  
Controlled Clinical Trials ◽  
Interferon Β ◽  
The World ◽  
Novel Coronavirus ◽  
Time Point

Since discovery of the novel coronavirus (SARS-CoV-2) in December of 2019, this viral pneumonia originated in Wuhan, China quickly spread around the world. This new disease, called COVID-19 can cause Acute Respiratory Distress Syndrome (ARDS) due to an uncontrolled inflammatory response like sepsis, that leads to multiple organ failure and even death. Several pharmacotherapeutics alternatives are being tested over the world, looking for most diverse drugs that might be able to fight the infection. The objective of this paper is to review the main pharmacotherapeutics techniques development, as remdesivir, chloroquine/hydroxychloroquine, lopinavir plus ritonavir, interferon-β, ivermectin, anticoagulants, convalescent plasma and vaccine, currently undergoing clinical trials in order to evaluate its effectiveness and safety to combat the COVID-19, presenting their characteristics, possible adverse effects and main scientific findings of its potential action. In conclusion, some therapies presented promising in-vitro results or in the treatment of some patients, nonetheless, multicentric blinded placebo controlled clinical trials are necessary to determine their effectiveness, safety, dosage, and best time point of treatment.

scholarly journals Proteasome inhibition as a therapeutic approach in atypical teratoid/rhabdoid tumors

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Andrew Morin ◽  
Caroline Soane ◽  
Angela Pierce ◽  
Bridget Sanford ◽  
Kenneth L Jones ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cell Lines ◽  
Proteasome Inhibitor ◽  
High Grade Glioma ◽  
Proteasome Inhibition ◽  
Atypical Teratoid ◽  
Rhabdoid Tumors ◽  
Approved Drugs

Abstract Background Atypical teratoid/thabdoid tumor (AT/RT) remains a difficult-to-treat tumor with a 5-year overall survival rate of 15%–45%. Proteasome inhibition has recently been opened as an avenue for cancer treatment with the FDA approval of bortezomib (BTZ) in 2003 and carfilzomib (CFZ) in 2012. The aim of this study was to identify and characterize a pre-approved targeted therapy with potential for clinical trials in AT/RT. Methods We performed a drug screen using a panel of 134 FDA-approved drugs in 3 AT/RT cell lines. Follow-on in vitro studies used 6 cell lines and patient-derived short-term cultures to characterize selected drug interactions with AT/RT. In vivo efficacy was evaluated using patient derived xenografts in an intracranial murine model. Results BTZ and CFZ are highly effective in vitro, producing some of the strongest growth-inhibition responses of the evaluated 134-drug panel. Marizomib (MRZ), a proteasome inhibitor known to pass the blood–brain barrier (BBB), also strongly inhibits AT/RT proteasomes and generates rapid cell death at clinically achievable doses in established cell lines and freshly patient-derived tumor lines. MRZ also significantly extends survival in an intracranial mouse model of AT/RT. Conclusions MRZ is a newer proteasome inhibitor that has been shown to cross the BBB and is already in phase II clinical trials for adult high-grade glioma (NCT NCT02330562 and NCT02903069). MRZ strongly inhibits AT/RT cell growth both in vitro and in vivo via a moderately well-characterized mechanism and has direct translational potential for patients with AT/RT.

scholarly journals Repurposing of FDA Approved Drugs for the Identification of Potential Inhibitors of SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Abhik Kumar Ray ◽  
Parth Sarthi Sen Gupta ◽  
Saroj Kumar Panda ◽  
Satyaranjan Biswal ◽  
Malay Kumar Rana
Keyword(s):  
Virtual Screening ◽  
Binding Energies ◽  
Great Promise ◽  
Main Protease ◽  
Promising Target ◽  
Inhibitory Potential ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Potential Inhibitors ◽  
Fda Approved Drugs

<p>COVID-19, responsible for several deaths, demands a cumulative effort of scientists worldwide to curb the pandemic. The main protease, responsible for the cleavage of the polyprotein and formation of replication complex in virus, is considered as a promising target for the development of potential inhibitors to treat the novel coronavirus. The effectiveness of FDA approved drugs targeting the main protease in previous SARS-COV (s) reported earlier indicates the chances of success for the repurposing of FDA drugs against SARS-COV-2. Therefore, in this study, molecular docking and virtual screening of FDA approved drugs, primarily of three categories: antiviral, antimalarial, and peptide, are carried out to investigate their inhibitory potential against the main protease. Virtual screening has identified 53 FDA drugs on the basis of their binding energies (< -7.0 kcal/mol), out of which the top two drugs Velpatasvir (-9.1 kcal/mol) and Glecaprevir (-9.0 kcal/mol) seem to have great promise. These drugs have a stronger affinity to the SARS-CoV-2 main protease than the crystal bound inhibitor α-ketoamide 13B (-6.7 kcal/mol) or Indinavir (-7.5 kcal/mol) that has been proposed in a recent study as one of the best drugs for SARS-CoV-2. The <i>in-silico</i> efficacies of the screened drugs could be instructive for further biochemical and structural investigation for repurposing. The molecular dynamics studies on the shortlisted drugs are underway. </p>

scholarly journals Potential Inhibitors Against Papain-like Protease of Novel Coronavirus (COVID-19) from FDA Approved Drugs

2020 ◽  
Author(s):  
Rimanshee Arya ◽  
Amit Das ◽  
Vishal Prashar ◽  
Mukesh Kumar
Keyword(s):  
Life Cycle ◽  
Active Site ◽  
Homology Model ◽  
Docking Studies ◽  
Rational Selection ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Potential Inhibitors ◽  
Fda Approved Drugs ◽  
Selection Of

<p>The cases of 2019 novel coronavirus (COVID-19) infection have been continuously increasing ever since its outbreak in China last December. Currently, there are no approved drugs to treat the infection. In this scenario, there is a need to utilize the existing repertoire of FDA approved drugs to treat the disease. The rational selection of these drugs could be made by testing their ability to inhibit any COVID-19 proteins essential for viral life-cycle. We chose one such crucial viral protein, the papain-like protease (PLpro), to screen the FDA approved drugs <i>in silico</i>. The homology model of the protease was built based on the SARS-coronavirus PLpro structure, and the drugs were docked in S3/S4 pockets of the active site of the enzyme. In our docking studies, fifteen FDA approved drugs, including chloroquine and formoterol, bind the target enzyme with significant affinity and good geometry, suggesting their potential to be utilized against the virus.</p>

scholarly journals In Silico Identification and Docking-Based Drug Repurposing Against the Main Protease of SARS-CoV-2, Causative Agent of COVID-19

2020 ◽  
Author(s):  
Yogesh Kumar ◽  
Harvijay Singh
Keyword(s):  
Virtual Screening ◽  
Active Site ◽  
Viral Infections ◽  
Drug Repurposing ◽  
Docking Study ◽  
Docking Studies ◽  
Main Protease ◽  
Novel Coronavirus ◽  
Approved Drugs

<div>The rapidly enlarging COVID-19 pandemic caused by novel SARS-coronavirus 2 is a global</div><div>public health emergency of unprecedented level. Therefore the need of a drug or vaccine that</div><div>counter SARS-CoV-2 is an utmost requirement at this time. Upon infection the ssRNA genome</div><div>of SARS-CoV-2 is translated into large polyprotein which further processed into different</div><div>nonstructural proteins to form viral replication complex by virtue of virus specific proteases:</div><div>main protease (3-CL protease) and papain protease. This indispensable function of main protease</div><div>in virus replication makes this enzyme a promising target for the development of inhibitors and</div><div>potential treatment therapy for novel coronavirus infection. The recently concluded α-ketoamide</div><div>ligand bound X-ray crystal structure of SARS-CoV-2 Mpro (PDB ID: 6Y2F) from Zhang et al.</div><div>has revealed the potential inhibitor binding mechanism and the determinants responsible for</div><div>involved molecular interactions. Here, we have carried out a virtual screening and molecular</div><div>docking study of FDA approved drugs primarily targeted for other viral infections, to investigate</div><div>their binding affinity in Mpro active site. Virtual screening has identified a number of antiviral</div><div>drugs, top ten of which on the basis of their bending energy score are further examined through </div><div>molecular docking with Mpro. Docking studies revealed that drug Lopinavir-Ritonavir, Tipranavir</div><div>and Raltegravir among others binds in the active site of the protease with similar or higher</div><div>affinity than the crystal bound inhibitor α-ketoamide. However, the in-vitro efficacies of the drug</div><div>molecules tested in this study, further needs to be corroborated by carrying out biochemical and</div><div>structural investigation. Moreover, this study advances the potential use of existing drugs to be</div><div>investigated and used to contain the rapidly expanding SARS-CoV-2 infection.</div>

scholarly journals Computational Molecular Docking and Virtual Screening Revealed Promising SARS-CoV-2 Drugs

2020 ◽  
Author(s):  
Maryam Hosseini ◽  
Wanqiu Chen ◽  
Charles Wang
Keyword(s):  
Molecular Docking ◽  
Binding Energy ◽  
Virtual Screening ◽  
Clinical Studies ◽  
Inhibitory Effect ◽  
Docking Approach ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Potential Inhibitors ◽  
Computational Molecular Docking

The pandemic of novel coronavirus disease 2019 (COVID-19) is rampaging the world with more than 1.4 million of confirmed cases and more than 85,000 of deaths across world by April 9th, 2020. There is an urgent need to identify effective drugs to fight against the virus. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belongs to the family of coronaviruses consisting of four structural and 16 non-structured proteins. Three non-structural proteins such as main protease, papain like protease, and RNA-dependent RNA polymerase are believed to play a crucial role in the virus replication. We applied a computational ligand-receptor binding modeling and performed a comprehensive virtual screening on the FDA-approved drugs against these three SARS-CoV-2 proteins using AutoDock Vina. Our computational studies indicated that Simeprevir, Ledipasvir, Idarubicin, Saquinavir, Ledipasivir, Partitaprevir, Glecaprevir, and Velpatasvir are all promising inhibitors, which displayed a lower binding energy (higher inhibitory effect) than Remdesivir, Lopinavir, and Ritonavir. However, we found that chloroquine and hydroxychloroquine, which showed efficacy in treating the COVID-19 in recent clinical studies, had high binding energy with all three proteins, suggesting they may work through a different mechanism. We also identified several novel drugs as potential inhibitors against SARS-CoV-2, including antiviral Raltegravir; antidiabetic Amaryl; antibiotics Retapamulin, Rifimixin, and Rifabutin; antiemetic Fosaprepitant and Netupitant. In summary, our computational molecular docking approach and virtual screening identified some promising candidate SARS-CoV-2 drugs that may be considered for further clinical studies.

scholarly journals Drug Repurposing and New Therapeutic Strategies for SARS-CoV-2 Disease Using a Novel Molecular Modeling-AI Hybrid Workflow

2020 ◽  
Author(s):  
Scott Bembenek
Keyword(s):  
Molecular Modeling ◽  
Therapeutic Targets ◽  
Drug Repurposing ◽  
Preclinical Research ◽  
Main Protease ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Usual Process ◽  
Potential Inhibitors ◽  
Computational Platform

<p>The recent<b> </b>outbreak of the novel coronavirus (SARS-CoV-2) poses a significant challenge to the scientific and medical communities to find immediate treatments. The usual process of identifying viable molecules and transforming them into a safe and effective drug takes 10-15 years, with around 5 years of that time spent in preclinical research and development alone. The fastest strategy is to identify existing drugs or late-stage clinical molecules (originally intended for other therapeutic targets) that already have some level of efficacy. To this end, we tasked our novel molecular modeling-AI hybrid computational platform with finding potential inhibitors of the SARS-CoV-2 main protease (M<sup>pro</sup>, 3CL<sup>pro</sup>). Over 13,000 FDA-approved drugs and clinical candidates (represented by just under 30,000 protomers) were examined. This effort resulted in the identification of several promising molecules. Moreover, it provided insight into key chemical motifs surely to be beneficial in the design of future inhibitors. Finally, it facilitated a unique perspective into other potentially therapeutic targets and pathways for SARS-CoV-2.</p>

Sign in / Sign up

Export Citation Format

Share Document