scholarly journals Assessment of FDA-approved drugs against Strongyloides ratti in vitro and in vivo to identify potentially active drugs against strongyloidiasis

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jennifer Keiser ◽  
Cécile Häberli
Keyword(s):  
Gentian Violet ◽  
Cetylpyridinium Chloride ◽  
Drug Repurposing ◽  
Strongyloides Stercoralis ◽  
In Vivo Studies ◽  
Benzethonium Chloride ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract Background Infections with Strongyloides stercoralis belong to the most neglected helminth diseases, and research and development (R&D) efforts on novel drugs are inadequate. Methods A commercially available library containing 1600 FDA-approved drugs was tested in vitro against Strongyloides ratti larvae (L3) at 100 µM. Hits (activity > 70%) were then evaluated against S. ratti adult worms at 10 µM. Morantel, prasterone, and levamisole were tested in the S. ratti rat model using dosages of 1–100 mg/kg. Results Seventy-one of the 1600 compounds tested against S. ratti L3 revealed activity above 70%. Of 64 compounds which progressed into the adult screen, seven compounds achieved death of all worms (benzethonium chloride, cetylpyridinium chloride, Gentian violet, methylbenzethonium chloride, morantel citrate, ivermectin, coumaphos), and another eight compounds had activity > 70%. Excluding topical and toxic compounds, three drugs progressed into in vivo studies. Prasterone lacked activity in vivo, while treatment with 100 mg/kg morantel and levamisole cured all rats. The highest in vivo activity was observed with levamisole, yielding a median effective dose (ED50) of 1.1 mg/kg. Conclusions Using a drug repurposing approach, our study identified levamisole as a potential backup drug for strongyloidiasis. Levamisole should be evaluated in exploratory clinical trials. Graphical Abstract

scholarly journals Sulfisoxazole does not inhibit the secretion of small extracellular vesicles

2020 ◽  
Author(s):  
Pamali Fonseka ◽  
Sai V Chitti ◽  
Rahul Sanwlani ◽  
Suresh Mathivanan
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Breast Cancer Cells ◽  
Drug Repurposing ◽  
Tumor Burden ◽  
Immunocompetent Mouse ◽  
Approved Drugs ◽  
Fda Approved Drugs

AbstractRecently, the study by Im et al. focused on blocking the release of extracellular vesicles (EVs) by cancer cells, as a strategy to block metastasis, by deploying a drug repurposing screen. Upon screening the library of FDA approved drugs in breast cancer cells in vitro, the authors reported the ability of the antibiotic Sulfisoxazole (SFX) in inhibiting EV biogenesis and secretion. SFX was also effective in reducing breast primary tumor burden and blocking metastasis in immunocompromised and immunocompetent mouse models. As we seek a compound to block EV biogenesis and secretion in our current in vivo studies, we intended to use SFX and hence performed in vitro characterization as the first step. However, treatment of two cancer cells with SFX did not reduce the amount of EVs as reported by the authors.

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.

Selection of Active Antiviral Compounds Against Covid-19 Disease Targeting Coronavirus Endoribonuclease Nendou/NSP15 Via Ligand- Based Virtual Screening and Molecular Docking

2020 ◽  
Vol 17 ◽  
Author(s):  
Gaurav Joshi ◽  
Ramarao Poduri
Keyword(s):  
Virtual Screening ◽  
Drug Repurposing ◽  
Antiviral Compounds ◽  
Clinical Level ◽  
Rapid Spread ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Selection Of

Background: The rapid spread of SARS-CoV-2 has caused havoc and panic among individuals, which has further worsened due to the unavailability of a proven drug(s) regime. Objective: The current work involves drug repurposing from the pool of USFDA approved drugs involving in silico virtual screening technique against Covid-19. Methods: Methodology involves virtual screening of 8548 FDA approved drugs against target protein endoribonuclease NendoU (Nsp15) (PDB ID: 6VWW). Results: Virtual screening-based analysis enabled us to identify four drugs, Eprosartan, Inarigivir soproxil, Foretinib, and DB01813 that could plausibly target Nsp15 against Covid-19 disease. Conclusion: The work offers the scope to corroborate the findings via in vitro and in vivo techniques to identify the potential of selected leads against Covid-19. The outcome may also help in tracing their molecular mechanism(s) in addition to their development at the clinical level in the future.

scholarly journals Virtual Drug Repurposing Study Against SARS-CoV-2 TMPRSS2 Target

2020 ◽  
Author(s):  
Serdar Durdagi
Keyword(s):  
Clinical Investigation ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Positive Control ◽  
New Drugs ◽  
In Vivo Studies ◽  
Approved Drugs

<p>Currently, the world suffers from a new coronavirus SARS-CoV-2 that causes COVID-19. Therefore, there is a need for the urgent development of novel drugs and vaccines for COVID-19. Since it can take years to develop new drugs against this disease, here we used a hybrid combined molecular modeling approach in virtual drug screening repurposing study to identify new compounds against this disease. One of the important SARS-CoV-2 targets namely type 2 transmembrane serine protease (TMPRSS2) was screened with NPC’s NIH small molecule library which includes approved drugs by FDA and compounds in clinical investigation. We used 6654 small molecules in molecular docking and top-50 docking scored compounds were initially used in short (10-ns) molecular dynamics (MD) simulations. Based on average MM/GBSA binding free energy results, long (100-ns) MD simulations were employed for the identified hits. Both binding energy results as well as crucial residues in ligand binding were also compared with a positive control TMPRSS2 inhibitor, Camostat mesylate. Based on these numerical calculations we proposed a compound (benzquercin) as strong TMPRSS2 inhibitor. If these results can be validated by in vitro and in vivo studies, benzquercin can be considered to be used as inhibitor of TMPRSS2 at the clinical studies.</p>

scholarly journals Pharmacophore Investigations of Potential COVID-19 RNA Polymerase (Rdrp) Inhibitors: Repurposing FDA-Approved Drugs

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Valentina L. Kouznetsova ◽  
Caroline Kellogg ◽  
Aidan Zhang ◽  
Mahidhar Tatineni ◽  
Mark A. Miller ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Hydrophobic Interactions ◽  
Pharmacophore Model ◽  
In Vivo Studies ◽  
Drug Candidates ◽  
Promising Target ◽  
Approved Drugs ◽  
Fda Approved Drugs

Authors: Valentina L. Kouznetsova, Caroline Kellogg, Aidan Zhang, Mahidhar Tatineni, Mark A. Miller, Igor F. Tsigelny Background: SARS-CoV-2 has caused tens of millions of infections worldwide and millions of deaths. Currently, no effective treatment has been identified against the virus. Of its viral proteins, the RNA-dependent RNA polymerase (RdRp) is a promising target for drug design because of its importance in the replication of the virus. Material and Methods: After the identification of an RdRp pocket site based on the crystal structure of the RdRp– nsp7–nsp8 complex and the triphosphate form of remdesivir (PDB ID: 7BV2), we created a pharmacophore model consisting of 11 different features. These features include two acceptors, three donors, one acceptor and donor, three donor or acceptor, and one hydrophobic; an excluded volume of R=1.1 Å was also added. We then ran a pharmacophore search on our conformational database (DB) of approximately 2500 FDA-approved drugs and 600 000 conformations to identify potential drug-candidates. To determine the drugs that bound the best, we conducted multi conformational docking of these results to the previously identified pocket site. Results: The pharmacophore search found 315 different potential inhibitors of RdRp, of which 85 were chosen based on the number of H-bonds and hydrophobic interactions in the best docking pose. Several of the drugs selected, including ritonavir, dasatinib, imatinib, and sofosbuvir, have previously been shown to be effective against other viruses. Conclusions: These findings highlight compounds that could lead to both in vitro and in vivo studies to identify potential treatments against SARS-CoV-2.

scholarly journals Virtual Drug Repurposing Study Against SARS-CoV-2 TMPRSS2 Target

2020 ◽  
Author(s):  
Serdar Durdagi
Keyword(s):  
Clinical Investigation ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Positive Control ◽  
New Drugs ◽  
In Vivo Studies ◽  
Approved Drugs

<p>Currently, the world suffers from a new coronavirus SARS-CoV-2 that causes COVID-19. Therefore, there is a need for the urgent development of novel drugs and vaccines for COVID-19. Since it can take years to develop new drugs against this disease, here we used a hybrid combined molecular modeling approach in virtual drug screening repurposing study to identify new compounds against this disease. One of the important SARS-CoV-2 targets namely type 2 transmembrane serine protease (TMPRSS2) was screened with NPC’s NIH small molecule library which includes approved drugs by FDA and compounds in clinical investigation. We used 6654 small molecules in molecular docking and top-50 docking scored compounds were initially used in short (10-ns) molecular dynamics (MD) simulations. Based on average MM/GBSA binding free energy results, long (100-ns) MD simulations were employed for the identified hits. Both binding energy results as well as crucial residues in ligand binding were also compared with a positive control TMPRSS2 inhibitor, Camostat mesylate. Based on these numerical calculations we proposed a compound (benzquercin) as strong TMPRSS2 inhibitor. If these results can be validated by in vitro and in vivo studies, benzquercin can be considered to be used as inhibitor of TMPRSS2 at the clinical studies.</p>

scholarly journals FDA Approved Drugs and Herbal Based Inhibitors Target SARS CoV-2 RNA Dependent RNA Polymerase

2021 ◽  
Vol 11 (3) ◽  
pp. 3811-3821
Keyword(s):  
Rna Polymerase ◽  
Drug Repurposing ◽  
World Health ◽  
In Vivo Studies ◽  
Rna Dependent Rna Polymerase ◽  
Novel Coronavirus ◽  
Health Organization ◽  
Approved Drugs

The recent outburst of COVID-19 started as an epidemic in Wuhan city, China, in December 2019. It was declared a pandemic by World Health Organization on 30 January 2020. The rapid spread of the novel coronavirus leads to more deaths worldwide. Also, it has spared many lives in its second wave of disease in many countries. Although scientists had produced vaccines, it does not suit every human being, and they are getting infected again, which is due to a lack of extensive clinical trials. Also, drug repurposing is ineffective. There is a need for more research; using in silico methods may be the better option in the current situation to save the lives of virus-affected individuals. The drugs used for other diseases and herbal compounds might help target the coronavirus. In this study, a protein, RNA-dependent RNA polymerase (RdRp), was chosen as a target from the virus for molecular docking. It was docked against several drugs on the market and also several herbal compounds. This study will help further in vitro and in vivo studies with new lead compounds, new horizons for drugs in trials, and a new approach for Insilco analysis to treat COVID-19.

scholarly journals A platform utilizing Drosophila ovulation for nonhormonal contraceptive screening

2021 ◽  
Vol 118 (28) ◽  
pp. e2026403118
Author(s):  
Kewa Jiang ◽  
Jiyang Zhang ◽  
Yuping Huang ◽  
Yingzheng Wang ◽  
Shuo Xiao ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Unmet Need ◽  
Dependent Manner ◽  
Female Reproduction ◽  
Contraceptive Agents ◽  
Follicle Rupture ◽  
Approved Drugs ◽  
Fda Approved Drugs

A significant unmet need for new contraceptive options for both women and men remains due to side-effect profiles, medical concerns, and the inconvenience of many currently available contraceptive products. Unfortunately, the development of novel nonsteroidal female contraceptive medicine has been stalled in the last couple of decades due to the lack of effective screening platforms. Drosophila utilizes conserved signaling pathways for follicle rupture, a final step in ovulation that is essential for female reproduction. Therefore, we explored the potential to use Drosophila as a model to screen compounds that could inhibit follicle rupture and be nonsteroidal contraceptive candidates. Using our ex vivo follicle rupture assay, we screened 1,172 Food and Drug Administration (FDA)–approved drugs and identified six drugs that could inhibit Drosophila follicle rupture in a dose-dependent manner. In addition, we characterized the molecular actions of these drugs in the inhibition of adrenergic signaling and follicle rupture. Furthermore, we validated that three of the four drugs consistently inhibited mouse follicle rupture in vitro and that two of them did not affect progesterone production. Finally, we showed that chlorpromazine, one of the candidate drugs, can significantly inhibit mouse follicle rupture in vivo. Our work suggests that Drosophila ovulation is a valuable platform for identifying lead compounds for nonsteroidal contraceptive development and highlights the potential of these FDA-approved drugs as novel nonsteroidal contraceptive agents.

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.

Potential Papain-like Protease Inhibitors against COVID-19: A Comprehensive In Silico Based Review

2021 ◽  
Vol 25 ◽  
Author(s):  
Neetu Agrawal ◽  
Shilpi Pathak ◽  
Ahsas Goyal
Keyword(s):  
In Silico ◽  
Chemical Compounds ◽  
Potential Candidate ◽  
In Vivo Experiments ◽  
Drug Databases ◽  
In Silico Studies ◽  
Approved Drugs ◽  
Fda Approved Drugs

: The entire world has been in a battle against the COVID-19 pandemic since its first appearance in December 2019. Thus researchers are desperately working to find an effective and safe therapeutic agent for its treatment. The multifunctional coronavirus enzyme papain-like protease (PLpro) is a potential target for drug discovery to combat the ongoing pandemic responsible for cleavage of the polypeptide, deISGylation, and suppression of host immune response. The present review collates the in silico studies performed on various FDA-approved drugs, chemical compounds, and phytochemicals from various drug databases and represents the compounds possessing the potential to inhibit PLpro. Thus this review can provide quick access to a potential candidate to medicinal chemists to perform in vitro and in vivo experiments who are thriving to find the effective agents for the treatment of COVID-19.

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