8 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2020/09/09

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

In Silico Drug Repurposing for SARS-CoV-2 Main Proteinase and Spike Proteins.

J Proteome Res. 2020 Sep 07;:

Authors: Maffucci I, Contini A

Abstract
The pandemic caused by SARS-CoV-2 is currently representing a major health and economic threat to humanity. So far, no specific treatment to this viral infection has been developed and the emergency still requires an efficient intervention. In this work, we used virtual screening to facilitate drug repurposing against SARS-CoV-2, targeting viral main proteinase and spike protein with 3000 existing drugs. We used a protocol based on a docking step followed by a short molecular dynamic simulation and rescoring by the Nwat-MMGBSA approach. Our results provide suggestions for prioritizing in vitro and/or in vivo tests of already available compounds.

PMID: 32893632 [PubMed - as supplied by publisher]

Ivermectin Docks to the SARS-CoV-2 Spike Receptor-binding Domain Attached to ACE2.

In Vivo. 2020 Sep-Oct;34(5):3023-3026

Authors: Lehrer S, Rheinstein PH

Abstract
BACKGROUND/AIM: Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). One drug that has attracted interest is the antiparasitic compound ivermectin, a macrocyclic lactone derived from the bacterium Streptomyces avermitilis. We carried out a docking study to determine if ivermectin might be able to attach to the SARS-CoV-2 spike receptor-binding domain bound with ACE2.
MATERIALS AND METHODS: We used the program AutoDock Vina Extended to perform the docking study.
RESULTS: Ivermectin docked in the region of leucine 91 of the spike and histidine 378 of the ACE2 receptor. The binding energy of ivermectin to the spike-ACE2 complex was -18 kcal/mol and binding constant was 5.8 e-08.
CONCLUSION: The ivermectin docking we identified may interfere with the attachment of the spike to the human cell membrane. Clinical trials now underway should determine whether ivermectin is an effective treatment for SARS-Cov2 infection.

PMID: 32871846 [PubMed - indexed for MEDLINE]

Systematic Review on Repurposing Use of Favipiravir Against SARS-CoV-2.

Mymensingh Med J. 2020 Jul;29(3):747-754

Authors: Nasir M, Perveen RA, Saha SK, Talha KA, Selina F, Islam MA

Abstract
The sudden outbreak of a novel coronavirus in 2019 in Wuhan, China, that rapidly provoked a global concern, marked as the third attack of corona virus in the human society that affected the global healthcare system as well as the global economy. Until and unless an effective vaccine is discovered against the virus, the pharmacological intervention by different antivirals is in the run for remedy. The aim of this systematic review was to evaluate the role of favipiravir along with its safety and efficacy for the patients who are suffering from severe acute respiratory distress syndrome due to CoronaVirus-2 (SARS-CoV-2) as re-purposeful use. We searched PubMed, EMBASE for randomized controlled trials (RCTs), cilicaltrial.com for registered on going trails to evaluate the pros and cons of using favipiravir in COVID-19. After vigorous searching, screening and sorting of 314 articles for completed and published scientific evidences in electronic database, there were only 2 completed and published randomized control trials (RCT) and 17 ongoing or unpublished trials found until June 2020. The main outcome measures were viral clearance, clinical improvement and adverse events reported and published on 147 patients infected with SARS-CoV2. The 2 completed RCTs showed significantly better treatment effects on disease progression, viral clearance, improved the latency to relief for pyrexia and cough on favipiravir treated patients. Adverse effects caused Favipiravir are mild and manageable. Although 9 more RCTs and cohort studies are supposed to be completed by this time that may unveil some evidence for use of anti-RNA-viral drug favipiravir against influenza or Ebola to re-purposing against COVID-19 as adopted in different treatment guidelines.

PMID: 32844821 [PubMed - indexed for MEDLINE]

In vitro evaluation of antiviral activity of single and combined repurposable drugs against SARS-CoV-2.

Antiviral Res. 2020 09;181:104878

Authors: Pizzorno A, Padey B, Dubois J, Julien T, Traversier A, Dulière V, Brun P, Lina B, Rosa-Calatrava M, Terrier O

Abstract
In response to the current pandemic caused by the novel SARS-CoV-2, identifying and validating effective therapeutic strategies is more than ever necessary. We evaluated the in vitro antiviral activities of a shortlist of compounds, known for their cellular broad-spectrum activities, together with drugs that are currently under evaluation in clinical trials for COVID-19 patients. We report the antiviral effect of remdesivir, lopinavir, chloroquine, umifenovir, berberine and cyclosporine A in Vero E6 cells model of SARS-CoV-2 infection, with estimated 50% inhibitory concentrations of 0.99, 5.2, 1.38, 3.5, 10.6 and 3 μM, respectively. Virus-directed plus host-directed drug combinations were also investigated. We report a strong antagonism between remdesivir and berberine, in contrast with remdesivir/diltiazem, for which we describe high levels of synergy, with mean Loewe synergy scores of 12 and peak values above 50. Combination of host-directed drugs with direct acting antivirals underscore further validation in more physiological models, yet they open up interesting avenues for the treatment of COVID-19.

PMID: 32679055 [PubMed - indexed for MEDLINE]

The Effect of Ultraviolet C Radiation Against Different N95 Respirators Inoculated with SARS-CoV-2.

Int J Infect Dis. 2020 Sep 03;:

Authors: Ozog DM, Sexton JZ, Narla S, Pretto-Kernahan CD, Mirabelli C, Lim HW, Hamzavi IH, Tibbetts RJ, Mi QS

Abstract
OBJECTIVES: There are currently no studies that have examined whether one dosage can be uniformly applied to different respirator types to effectively decontaminate SARS-CoV-2 on N95 filtering facepiece respirators (FFRs). Health care workers have been using this disinfection method during the pandemic. Our objective was to determine the effect of UVC on SARS-CoV-2 inoculated N95 respirators and whether this was respirator material/model type dependent.
METHODS: Four different locations (facepiece and strap) on 5 different N95 FFR models (3 M 1860, 8210, 8511, 9211; Moldex 1511) were inoculated with a 10 μL drop of SARS-CoV-2 viral stock (8 × 107 TCID50/mL). The outside-facing and wearer-facing surfaces of the respirators were each irradiated with a dose of 1.5 J/cm2 UVC (254 nm). Viable SARS-CoV-2 was quantified by a median tissue culture infectious dose assay (TCID50).
RESULTS: UVC delivered using a dose of 1.5 J/cm2, to each side, was an effective method of decontamination for the facepieces of 3 M 1860 and Moldex 1511, and for the straps of 3 M 8210 and the Moldex 1511.
CONCLUSION: This dose is an appropriate decontamination method to facilitate reuse of respirators for healthcare personnel when applied to certain models/materials. In addition, some straps may require additional disinfection to maximize the safety to frontline workers. Implementation of widespread UVC decontamination methods requires a careful consideration of model, material type, design, and fit-testing following irradiation.

PMID: 32891736 [PubMed - as supplied by publisher]

Development of a minimal physiologically-based pharmacokinetic model to simulate lung exposure in humans following oral administration of ivermectin for COVID-19 drug repurposing.

J Pharm Sci. 2020 Sep 03;:

Authors: Jermain B, Hanafin PO, Cao Y, Lifschitz A, Lanusse C, Rao G

Abstract
SARS-CoV-2 utilizes the IMPα/β1 heterodimer to enter host cell nuclei after gaining cellular access through the ACE2 receptor. Ivermectin has shown antiviral activity by inhibiting the formation of the importin-α (IMPα) and IMPβ1 subunits as well as dissociating the IMPα/β1 heterodimer and has in vitro efficacy against SARS-CoV-2. Plasma and lung ivermectin concentrations vs. time profiles in cattle were used to determine the apparent plasma to lung tissue partition coefficient of ivermectin. This coefficient, together with a simulated geometric mean plasma profile of ivermectin from a published population pharmacokinetic model, was utilized to develop a minimal physiologically-based pharmacokinetic (mPBPK) model. The mPBPK model accurately described the simulated ivermectin plasma concentration profile in humans. The mPBPK model was also used to simulate human lung exposure to ivermectin after 12, 30, and 120 mg oral doses. The simulated ivermectin lung exposures reached a maximum concentration of 772 ng/mL, far less than the estimated 1750 ng/mL IC50 reported for ivermectin against SARS-CoV-2 in vitro. Further studies of ivermectin either reformulated for inhaled delivery or in combination with other antivirals with differing mechanisms of action is needed to assess its therapeutic potential.

PMID: 32891630 [PubMed - as supplied by publisher]

Drug repurposing approach to fight COVID-19.

Pharmacol Rep. 2020 Sep 05;:

Authors: Singh TU, Parida S, Lingaraju MC, Kesavan M, Kumar D, Singh RK

Abstract
Currently, there are no treatment options available for the deadly contagious disease, coronavirus disease 2019 (COVID-19). Drug repurposing is a process of identifying new uses for approved or investigational drugs and it is considered as a very effective strategy for drug discovery as it involves less time and cost to find a therapeutic agent in comparison to the de novo drug discovery process. The present review will focus on the repurposing efficacy of the currently used drugs against COVID-19 and their mechanisms of action, pharmacokinetics, dosing, safety, and their future perspective. Relevant articles with experimental studies conducted in-silico, in-vitro, in-vivo, clinical trials in humans, case reports, and news archives were selected for the review. Number of drugs such as remdesivir, favipiravir, ribavirin, lopinavir, ritonavir, darunavir, arbidol, chloroquine, hydroxychloroquine, tocilizumab and interferons have shown inhibitory effects against the SARS-CoV2 in-vitro as well as in clinical conditions. These drugs either act through virus-related targets such as RNA genome, polypeptide packing and uptake pathways or target host-related pathways involving angiotensin-converting enzyme-2 (ACE2) receptors and inflammatory pathways. Using the basic knowledge of viral pathogenesis and pharmacodynamics of drugs as well as using computational tools, many drugs are currently in pipeline to be repurposed. In the current scenario, repositioning of the drugs could be considered the new avenue for the treatment of COVID-19.

PMID: 32889701 [PubMed - as supplied by publisher]

Drug repurposing for cancer treatments: a well-intentioned, but misguided strategy.

Lancet Oncol. 2020 Sep;21(9):1134-1136

Authors: Tran AA, Prasad V

PMID: 32888447 [PubMed - as supplied by publisher]

Drug Repurposing in Dentistry; towards Application of Small Molecules in Dentin Repair.

Int J Mol Sci. 2020 Sep 02;21(17):

Authors: Birjandi AA, Suzano FR, Sharpe PT

Abstract
One of the main goals of dentistry is the natural preservation of the tooth structure following damage. This is particularly implicated in deep dental cavities affecting dentin and pulp, where odontoblast survival is jeopardized. This activates pulp stem cells and differentiation of new odontoblast-like cells, accompanied by increased Wnt signaling. Our group has shown that delivery of small molecule inhibitors of GSK3 stimulates Wnt/β-catenin signaling in the tooth cavity with pulp exposure and results in effective promotion of dentin repair. Small molecules are a good therapeutic option due to their ability to pass across cell membranes and reach target. Here, we investigate a range of non-GSK3 target small molecules that are currently used for treatment of various medical conditions based on other kinase inhibitory properties. We analyzed the ability of these drugs to stimulate Wnt signaling activity by off-target inhibition of GSK3. Our results show that a c-Met inhibitor, has the ability to stimulate Wnt/β-catenin pathway in dental pulp cells in vitro at low concentrations. This work is an example of drug repurposing for dentistry and suggests a candidate drug to be tested in vivo for natural dentin repair. This approach bypasses the high level of economical and time investment that are usually required in novel drug discoveries.

PMID: 32887519 [PubMed - as supplied by publisher]

Identification of promising antiviral drug candidates against non-structural protein 15 (NSP15) from SARS-CoV-2: an in silico assisted drug-repurposing study.

J Biomol Struct Dyn. 2020 Sep 04;:1-11

Authors: Khan RJ, Jha RK, Singh E, Jain M, Amera GM, Singh RP, Muthukumaran J, Singh AK

Abstract
The recent COVID-19 pandemic caused by SARS-CoV-2 has recorded a high number of infected people across the globe. The virulent nature of the virus makes it necessary for us to identify promising therapeutic agents in a time-sensitive manner. The current study utilises an in silico based drug repurposing approach to identify potential anti-viral drug candidates targeting non-structural protein 15 (NSP15), i.e. a uridylate specific endoribonuclease of SARS-CoV-2 which plays an indispensable role in RNA processing and viral immune evasion from the host immune system. The NSP15 protein was screened against an in-house library of 123 antiviral drugs obtained from the DrugBank database from which three promising drug candidates were identified based on their estimated binding affinities (ΔG), estimated inhibition constants (Ki), the orientation of drug molecules in the active site and the key interacting residues of NSP15. Molecular dynamics (MD) simulations were performed for the screened drug candidates in complex with NSP15 as well as the apo form of NSP15 to mimic their physiological states. Based on the stable MD simulation trajectories, the binding free energies of the screened NSP15-drug complexes were calculated using the MM/PBSA approach. Two candidate drugs, Simeprevir and Paritaprevir, achieved the lowest binding free energies for NSP15, with a value of -259.522 ± 17.579 and -154.051 ± 33.628 kJ/mol, respectively. In addition, their complexes with NSP15 also exhibited the strongest structural stabilities. Taken together, we propose that Simeprevir and Paritaprevir are promising drug candidates to inhibit NSP15 and may act as potential therapeutic agents against SARS-CoV-2. Communicated by Ramaswamy H. Sarma.

PMID: 32885740 [PubMed - as supplied by publisher]

Drugs Repurposed as Antiferroptosis Agents Suppress Organ Damage, Including AKI, by Functioning as Lipid Peroxyl Radical Scavengers.

J Am Soc Nephrol. 2020 02;31(2):280-296

Authors: Mishima E, Sato E, Ito J, Yamada KI, Suzuki C, Oikawa Y, Matsuhashi T, Kikuchi K, Toyohara T, Suzuki T, Ito S, Nakagawa K, Abe T

Abstract
BACKGROUND: Ferroptosis, nonapoptotic cell death mediated by free radical reactions and driven by the oxidative degradation of lipids, is a therapeutic target because of its role in organ damage, including AKI. Ferroptosis-causing radicals that are targeted by ferroptosis suppressors have not been unequivocally identified. Because certain cytochrome P450 substrate drugs can prevent lipid peroxidation via obscure mechanisms, we evaluated their antiferroptotic potential and used them to identify ferroptosis-causing radicals.
METHODS: Using a cell-based assay, we screened cytochrome P450 substrate compounds to identify drugs with antiferroptotic activity and investigated the underlying mechanism. To evaluate radical-scavenging activity, we used electron paramagnetic resonance-spin trapping methods and a fluorescence probe for lipid radicals, NBD-Pen, that we had developed. We then assessed the therapeutic potency of these drugs in mouse models of cisplatin-induced AKI and LPS/galactosamine-induced liver injury.
RESULTS: We identified various US Food and Drug Administration-approved drugs and hormones that have antiferroptotic properties, including rifampicin, promethazine, omeprazole, indole-3-carbinol, carvedilol, propranolol, estradiol, and thyroid hormones. The antiferroptotic drug effects were closely associated with the scavenging of lipid peroxyl radicals but not significantly related to interactions with other radicals. The elevated lipid peroxyl radical levels were associated with ferroptosis onset, and known ferroptosis suppressors, such as ferrostatin-1, also functioned as lipid peroxyl radical scavengers. The drugs exerted antiferroptotic activities in various cell types, including tubules, podocytes, and renal fibroblasts. Moreover, in mice, the drugs ameliorated AKI and liver injury, with suppression of tissue lipid peroxidation and decreased cell death.
CONCLUSIONS: Although elevated lipid peroxyl radical levels can trigger ferroptosis onset, some drugs that scavenge lipid peroxyl radicals can help control ferroptosis-related disorders, including AKI.

PMID: 31767624 [PubMed - indexed for MEDLINE]

Multiomics dissection of molecular regulatory mechanisms underlying autoimmune-associated noncoding SNPs.

JCI Insight. 2020 Sep 03;5(17):

Authors: Chen XF, Guo MR, Duan YY, Jiang F, Wu H, Dong SS, Zhou XR, Thynn HN, Liu CC, Zhang L, Guo Y, Yang TL

Abstract
More than 90% of autoimmune-associated variants are located in noncoding regions, leading to challenges in deciphering the underlying causal roles of functional variants and genes and biological mechanisms. Therefore, to reduce the gap between traditional genetic findings and mechanistic understanding of disease etiologies and clinical drug development, it is important to translate systematically the regulatory mechanisms underlying noncoding variants. Here, we prioritized functional noncoding SNPs with regulatory gene targets associated with 19 autoimmune diseases by incorporating hundreds of immune cell-specific multiomics data. The prioritized SNPs are associated with transcription factor (TF) binding, histone modification, or chromatin accessibility, indicating their allele-specific regulatory roles. Their target genes are significantly enriched in immunologically related pathways and other known immunologically related functions. We found that 90.1% of target genes are regulated by distal SNPs involving several TFs (e.g., the DNA-binding protein CCCTC-binding factor [CTCF]), suggesting the importance of long-range chromatin interaction in autoimmune diseases. Moreover, we predicted potential drug targets for autoimmune diseases, including 2 genes (NFKB1 and SH2B3) with known drug indications on other diseases, highlighting their potential drug repurposing opportunities. Taken together, these findings may provide useful information for future experimental follow-up and drug applications on autoimmune diseases.

PMID: 32879140 [PubMed - in process]

Inhibition of Retinoblastoma Cell Growth by CEP1347 Through Activation of the P53 Pathway.

Anticancer Res. 2020 Sep;40(9):4961-4968

Authors: Togashi K, Okada M, Suzuki S, Sanomachi T, Seino S, Yamamoto M, Yamashita H, Kitanaka C

Abstract
BACKGROUND/AIM: Despite advances in treatment modalities, the visual prognosis of retinoblastoma still remains unsatisfactory, underscoring the need to develop novel therapeutic approaches.
MATERIALS AND METHODS: The effect on the growth of six human retinoblastoma cell lines and a normal human fibroblast cell line of CEP1347, a small-molecule kinase inhibitor originally developed for the treatment of Parkinson's disease and therefore with a known safety profile in humans, was examined. The role of the P53 pathway in CEP1347-induced growth inhibition was also investigated.
RESULTS: CEP1347 selectively inhibited the growth of retinoblastoma cell lines expressing murine double minute 4 (MDM4), a P53 inhibitor. Furthermore, CEP1347 reduced the expression of MDM4 and activated the P53 pathway in MDM4-expressing retinoblastoma cells, which was required for the inhibition of their growth by CEP1347.
CONCLUSION: We propose CEP1347 as a promising candidate for the treatment of retinoblastomas, where functional inactivation of P53 as a result of MDM4 activation is reportedly common.

PMID: 32878784 [PubMed - in process]

Phenothiazines and Selenocompounds: A Potential Novel Combination Therapy of Multidrug Resistant Cancer.

Anticancer Res. 2020 Sep;40(9):4921-4928

Authors: GajdÁcs M, NovÉ M, Csonka Á, Varga B, SanmartÍn C, DomÍnguez-Álvarez E, Spengler G

Abstract
BACKGROUND/AIM: Phenothiazines constitute a versatile family of compounds in terms of biological activity, which have also gained a considerable attention in cancer research.
MATERIALS AND METHODS: Three phenothiazines (promethazine, chlorpromazine and thioridazine) have been tested in combination with 11 active selenocompounds against MDR (ABCB1-overexpressing) mouse T-lymphoma cells to investigate their activity as combination chemotherapy and as antitumor adjuvants in vitro with a checkerboard combination assay.
RESULTS: Seven selenocompounds showed toxicity on mouse embryonic fibroblasts, while three showed selectivity towards tumor cells. Two compounds showed synergism with all tested phenothiazines in low concentration ranges (1.46-11.25 μM). Thioridazine was the most potent among the three phenothiazines.
CONCLUSION: Phenothiazines belonging to different generations showed different levels of adjuvant activities. All the tested phenothiazines are already approved medicines with known pharmacological and toxicity profiles, therefore, their use as adjuvants in cancer may be considered as a potential drug repurposing strategy.

PMID: 32878780 [PubMed - in process]

Repurposing Quinacrine for Treatment of Malignant Mesothelioma: In-Vitro Therapeutic and Mechanistic Evaluation.

Int J Mol Sci. 2020 Aug 31;21(17):

Authors: Kulkarni NS, Vaidya B, Parvathaneni V, Bhanja D, Gupta V

Abstract
Malignant mesothelioma (MM) is a rare type of cancer primarily affecting mesothelial cells lining the pleural cavity. In this study, we propose to repurpose quinacrine (QA), a widely approved anti-malarial drug, for Malignant Pleural Mesothelioma (MPM) treatment. QA demonstrates high degree of cytotoxicity against both immortalized and primary patient-derived cell lines with sub-micromolar 50% inhibitory concentration (IC50) values ranging from 1.2 µM (H2452) to 5.03 µM (H28). Further, QA also inhibited cellular migration and colony formation in MPM cells, demonstrated using scratch and clonogenic assays, respectively. A 3D-spheroid cell culture experiment was performed to mimic in-vivo tumor conditions, and QA was reported to be highly effective in this simulated cellular model. Anti-angiogenic properties were also discovered for QA. Autophagy inhibition assay was performed, and results revealed that QA successfully inhibited autophagy process in MPM cells, which has been cited to be one of the survival pathways for MPM. Annexin V real-time apoptosis study revealed significant apoptotic induction in MPM cells following QA treatment. Western blots confirmed inhibition of autophagy and induction of apoptosis. These studies highlight anti-mesothelioma efficacy of QA at low doses, which can be instrumental in developing it as a stand-alone treatment strategy for MPM.

PMID: 32878257 [PubMed - in process]

8 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2020/09/03

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

10 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2020/09/02

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

9 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2020/09/02

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

SARS-CoV-2 E protein is a potential ion channel that can be inhibited by Gliclazide and Memantine.

Biochem Biophys Res Commun. 2020 09 10;530(1):10-14

Authors: Singh Tomar PP, Arkin IT

Abstract
COVID-19 is one of the most impactful pandemics in recorded history. As such, the identification of inhibitory drugs against its etiological agent, SARS-CoV-2, is of utmost importance, and in particular, repurposing may provide the fastest route to curb the disease. As the first step in this route, we sought to identify an attractive and viable target in the virus for pharmaceutical inhibition. Using three bacteria-based assays that were tested on known viroporins, we demonstrate that one of its essential components, the E protein, is a potential ion channel and, therefore, is an excellent drug target. Channel activity was demonstrated for E proteins in other coronaviruses, providing further emphasis on the importance of this functionally to the virus' pathogenicity. The results of a screening effort involving a repurposing drug library of ion channel blockers yielded two compounds that inhibit the E protein: Gliclazide and Memantine. In conclusion, as a route to curb viral virulence and abate COVID-19, we point to the E protein of SARS-CoV-2 as an attractive drug target and identify off-label compounds that inhibit it.

PMID: 32828269 [PubMed - indexed for MEDLINE]