6 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 2020/12/04

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.

Drug repurposing in oncology - Authors' reply.

Lancet Oncol. 2020 Dec;21(12):e544

Authors: Tran AA, Prasad V

PMID: 33271101 [PubMed - as supplied by publisher]

Drug repurposing in oncology.

Lancet Oncol. 2020 Dec;21(12):e543

Authors: Frantzi M, Latosinska A, Mokou M, Mischak H, Vlahou A

PMID: 33271100 [PubMed - as supplied by publisher]

Drug repurposing in oncology.

Lancet Oncol. 2020 Dec;21(12):e542

Authors: Bouche G, Gedye C, Meheus L, Pantziarka P

PMID: 33271099 [PubMed - as supplied by publisher]

COMPARE Analysis, a Bioinformatic Approach to Accelerate Drug Repurposing against Covid-19 and Other Emerging Epidemics.

SLAS Discov. 2020 Dec 02;:2472555220975672

Authors: Naasani I

Abstract
A novel bioinformatic approach for drug repurposing against emerging viral epidemics like Covid-19 is described. It exploits the COMPARE algorithm, a public program from the National Cancer Institute (NCI) to sort drugs according to their patterns of growth inhibitory profiles from a diverse panel of human cancer cell lines. The data repository of the NCI includes the growth inhibitory patterns of more than 55,000 molecules. When candidate drug molecules with ostensible anti-SARS-CoV-2 activities were used as seeds (e.g., hydroxychloroquine, ritonavir, and dexamethasone) in COMPARE, the analysis uncovered several molecules with fingerprints similar to the seeded drugs. Interestingly, despite the fact that the uncovered drugs were from various pharmacological classes (antiarrhythmic, nucleosides, antipsychotic, alkaloids, antibiotics, and vitamins), they were all reportedly known from published literature to exert antiviral activities via different modes, confirming that COMPARE analysis is efficient for predicting antiviral activities of drugs from various pharmacological classes. Noticeably, several of the uncovered drugs can be readily tested, like didanosine, methotrexate, vitamin A, nicotinamide, valproic acid, uridine, and flucloxacillin. Unlike pure in silico methods, this approach is biologically more relevant and able to pharmacologically correlate compounds regardless of their chemical structures. This is an untapped resource, reliable and readily exploitable for drug repurposing against current and future viral outbreaks.

PMID: 33267713 [PubMed - as supplied by publisher]

6 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 2020/12/03

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.

Drug2ways: Reasoning over causal paths in biological networks for drug discovery.

PLoS Comput Biol. 2020 Dec 02;16(12):e1008464

Authors: Rivas-Barragan D, Mubeen S, Guim Bernat F, Hofmann-Apitius M, Domingo-Fernández D

Abstract
Elucidating the causal mechanisms responsible for disease can reveal potential therapeutic targets for pharmacological intervention and, accordingly, guide drug repositioning and discovery. In essence, the topology of a network can reveal the impact a drug candidate may have on a given biological state, leading the way for enhanced disease characterization and the design of advanced therapies. Network-based approaches, in particular, are highly suited for these purposes as they hold the capacity to identify the molecular mechanisms underlying disease. Here, we present drug2ways, a novel methodology that leverages multimodal causal networks for predicting drug candidates. Drug2ways implements an efficient algorithm which reasons over causal paths in large-scale biological networks to propose drug candidates for a given disease. We validate our approach using clinical trial information and demonstrate how drug2ways can be used for multiple applications to identify: i) single-target drug candidates, ii) candidates with polypharmacological properties that can optimize multiple targets, and iii) candidates for combination therapy. Finally, we make drug2ways available to the scientific community as a Python package that enables conducting these applications on multiple standard network formats.

PMID: 33264280 [PubMed - as supplied by publisher]

DECODING INFORMATION ON COVID - 19: ONTOLOGICAL APPROACH TOWARDS DESIGN POSSIBLE THERAPEUTICS.

Inform Med Unlocked. 2020 Nov 27;:100486

Authors: Jayachandran SK, Anusuyadevi M, Essa MM, Qoronfleh MW

Abstract
To date, no effective preventive or curative medical interventions exist against COVID-19, caused by Severe Acute Respiratory Syndrome corona virus 2 (SARS CoV-2). The available interventions are only supportive and palliative in nature. Popular among the emerging explanations for the mortality from COVID-19 is "cytokine storm", attributed to the body's aggressive immune response to this novel pathogen. In less than a year the disease has spread to almost all countries, though the mortality rates have varied significantly from country to country based on factors such as the demographical mix of the population, prevalence of comorbidities, as well as prior exposure to viruses from the corona family. This review examines the current literature on mortality rates across the globe, explores the possible reasons, thereby decoding variations. COVID-19 researchers have noted unique characteristics in the structural and host-pathogen interaction and identified several possible target proteins and sites that could exhibit control over the entry of SARS CoV-2 into the host, which this paper reviews in detail. Identification of new targets, both in the virus and the host, may accelerate the search for effective vaccines and curative drugs against COVID-19. Further, the ontological approach of this review is likely to provide insights for researchers to anticipate and be ready for future mutant viruses that may emerge in future.

PMID: 33263073 [PubMed - as supplied by publisher]

Computational drug discovery and repurposing for the treatment of COVID-19: A systematic review.

Bioorg Chem. 2020 Nov 19;:104490

Authors: Mohamed K, Yazdanpanah N, Saghazadeh A, Rezaei N

Abstract
BACKGROUND: Since the beginning of the novel coronavirus (SARS-CoV-2) disease outbreak, there has been an increasing interest in finding a potential therapeutic agent for the disease. Considering the matter of time, the computational methods of drug repurposing offer the best chance of selecting one drug from a list of approved drugs for the life-threatening condition of COVID-19. The present systematic review aims to provide an overview of studies that have used computational methods for drug repurposing in COVID-19.
METHODS: We undertook a systematic search in five databases and included original articles in English that applied computational methods for drug repurposing in COVID-19.
RESULTS: Twenty-one original articles utilizing computational drug methods for COVID-19 drug repurposing were included in the systematic review. Regarding the quality of eligible studies, high-quality items including the use of two or more approved drug databases, analysis of molecular dynamic simulation, multi-target assessment, the use of crystal structure for the generation of the target sequence, and the use of AutoDock Vina combined with other docking tools occurred in about 52%, 38%, 24%, 48%, and 19% of included studies. Studies included repurposed drugs mainly against non-structural proteins of SARS-CoV2: the main 3C-like protease (Lopinavir, Ritonavir, Indinavir, Atazanavir, Nelfinavir, and Clocortolone), RNA-dependent RNA polymerase (Remdesivir and Ribavirin), and the papain-like protease (Mycophenolic acid, Telaprevir, Boceprevir, Grazoprevir, Darunavir, Chloroquine, and Formoterol). The review revealed the best-documented multi-target drugs repurposed by computational methods for COVID-19 therapy as follows: antiviral drugs commonly used to treat AIDS/HIV (Atazanavir, Efavirenz, and Dolutegravir Ritonavir, Raltegravir, and Darunavir, Lopinavir, Saquinavir, Nelfinavir, and Indinavir), HCV (Grazoprevir, Lomibuvir, Asunaprevir, Ribavirin, and Simeprevir), HBV (Entecavir), HSV (Penciclovir), CMV (Ganciclovir), and Ebola (Remdesivir), anticoagulant drug (Dabigatran), and an antifungal drug (Itraconazole).
CONCLUSIONS: The present systematic review provides a list of existing drugs that have the potential to influence SARS-CoV2 through different mechanisms of action. For the majority of these drugs, direct clinical evidence on their efficacy for the treatment of COVID-19 is lacking. Future clinical studies examining these drugs might come to conclude, which can be more useful to inhibit COVID-19 progression.

PMID: 33261845 [PubMed - as supplied by publisher]

Drug repurposing for the treatment of COVID-19: Pharmacological aspects and synthetic approaches.

Bioorg Chem. 2020 Nov 19;:104488

Authors: Batalha PN, Forezi LSM, Lima CGS, Pauli FP, Boechat FCS, de Souza MCBV, Cunha AC, Ferreira VF, da Silva FC

Abstract
In December 2019, a new variant of SARS-CoV emerged, the so-called acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus causes the new coronavirus disease (COVID-19) and has been plaguing the world owing to its unprecedented spread efficiency, which has resulted in a huge death toll. In this sense, the repositioning of approved drugs is the fastest way to an effective response to a pandemic outbreak of this scale. Considering these facts, in this review we provide a comprehensive and critical discussion on the chemical aspects surrounding the drugs currently being studied as candidates for COVID-19 therapy. We intend to provide the general chemical community with an overview on the synthetic/biosynthetic pathways related to such molecules, as well as their mechanisms of action against the evaluated viruses and some insights on the pharmacological interactions involved in each case. Overall, the review aims to present the chemical aspects of the main bioactive molecules being considered to be repositioned for effective treatment of COVID-19 in all phases, from the mildest to the most severe.

PMID: 33261844 [PubMed - as supplied by publisher]

Repositioning of Ligands That Target the Spike Glycoprotein as Potential Drugs for SARS-CoV-2 in an In Silico Study.

Molecules. 2020 Nov 29;25(23):

Authors: Ramírez-Salinas GL, Martínez-Archundia M, Correa-Basurto J, García-Machorro J

Abstract
The worldwide health emergency of the SARS-CoV-2 pandemic and the absence of a specific treatment for this new coronavirus have led to the use of computational strategies (drug repositioning) to search for treatments. The aim of this work is to identify FDA (Food and Drug Administration)-approved drugs with the potential for binding to the spike structural glycoprotein at the hinge site, receptor binding motif (RBM), and fusion peptide (FP) using molecular docking simulations. Drugs that bind to amino acids are crucial for conformational changes, receptor recognition, and fusion of the viral membrane with the cell membrane. The results revealed some drugs that bind to hinge site amino acids (varenicline, or steroids such as betamethasone while other drugs bind to crucial amino acids in the RBM (naldemedine, atovaquone, cefotetan) or FP (azilsartan, maraviroc, and difluprednate); saquinavir binds both the RBM and the FP. Therefore, these drugs could inhibit spike glycoprotein and prevent viral entry as possible anti-COVID-19 drugs. Several drugs are in clinical studies; by focusing on other pharmacological agents (candesartan, atovaquone, losartan, maviroc and ritonavir) in this work we propose an additional target: the spike glycoprotein. These results can impact the proposed use of treatments that inhibit the first steps of the virus replication cycle.

PMID: 33260370 [PubMed - in process]

6 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 2020/12/02

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.

13 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 2020/12/01

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.

FRMD6 has tumor suppressor functions in prostate cancer.

Oncogene. 2020 Nov 28;:

Authors: Haldrup J, Strand SH, Cieza-Borrella C, Jakobsson ME, Riedel M, Norgaard M, Hedensted S, Dagnaes-Hansen F, Ulhoi BP, Eeles R, Borre M, Olsen JV, Thomsen M, Kote-Jarai Z, Sorensen KD

Abstract
Available tools for prostate cancer (PC) prognosis are suboptimal but may be improved by better knowledge about genes driving tumor aggressiveness. Here, we identified FRMD6 (FERM domain-containing protein 6) as an aberrantly hypermethylated and significantly downregulated gene in PC. Low FRMD6 expression was associated with postoperative biochemical recurrence in two large PC patient cohorts. In overexpression and CRISPR/Cas9 knockout experiments in PC cell lines, FRMD6 inhibited viability, proliferation, cell cycle progression, colony formation, 3D spheroid growth, and tumor xenograft growth in mice. Transcriptomic, proteomic, and phospho-proteomic profiling revealed enrichment of Hippo/YAP and c-MYC signaling upon FRMD6 knockout. Connectivity Map analysis and drug repurposing experiments identified pyroxamide as a new potential therapy for FRMD6 deficient PC cells. Finally, we established orthotropic Frmd6 and Pten, or Pten only (control) knockout in the ROSA26 mouse prostate. After 12 weeks, Frmd6/Pten double knockouts presented high-grade prostatic intraepithelial neoplasia (HG-PIN) and hyperproliferation, while Pten single-knockouts developed only regular PIN lesions and displayed lower proliferation. In conclusion, FRMD6 was identified as a novel tumor suppressor gene and prognostic biomarker candidate in PC.

PMID: 33249427 [PubMed - as supplied by publisher]

Diamond Light Source: contributions to SARS-CoV-2 biology and therapeutics.

Biochem Biophys Res Commun. 2020 Nov 19;:

Authors: Walsh MA, Grimes JM, Stuart DI

Abstract
The impact of COVID-19 on public health and the global economy has led to an unprecedented research response, with a major emphasis on the development of safe vaccines and drugs. However, effective, safe treatments typically take over a decade to develop and there are still no clinically approved therapies to treat highly pathogenic coronaviruses. Repurposing of known drugs can speed up development and this strategy, along with the use of biologicals (notably monoclonal antibody therapy) and vaccine development programmes remain the principal routes to dealing with the immediate impact of COVID-19. Nevertheless, the development of broadly-effective highly potent antivirals should be a major longer term goal. Structural biology has been applied with enormous effect, with key proteins structurally characterised only weeks after the SARS-CoV-2 sequence was released. Open-access to advanced infrastructure for structural biology techniques at synchrotrons and high-end cryo-EM and NMR centres has brought these technologies centre-stage in drug discovery. We summarise the role of Diamond Light Source in responses to the pandemic and note the impact of the immediate release of results in fuelling an open-science approach to early-stage drug discovery.

PMID: 33248689 [PubMed - as supplied by publisher]

Inhaled route and anti-inflammatory action of ivermectin: Do they hold promise in fighting against COVID-19?

Med Hypotheses. 2020 Nov 05;:110364

Authors: Mittal N, Mittal R

Abstract
In an effort to curb the global pandemic due to coronavirus, the scientific community is exploring various treatment strategies with a special emphasis on drug repurposing. Ivermectin, an anti-helminthic drug is also being proposed for treatment and prevention of COVID-19. Ivermectin has demonstrated broad spectrum antiviral activity against both DNA and RNA viruses. Due to its potential to interfere with transport of SARS-CoV-2 nucleocapsid protein to nucleus, it is being proposed to have antiviral activity against this virus as well which has been confirmed in an in-vitro study. However, in-vitro to in-vivo extrapolation studies indicate an inability to achieve the desired IC50 levels of ivermectin after oral administration of doses up to 10 times higher than the approved anti-helminthic dose. In a modelling simulation study, drug accumulation in the lungs was noticed at levels having potential antiviral activity. It is hypothesised that inhaled formulation of ivermectin may be effective against SARS-CoV-2. Therefore, ivermectin administered via inhalational route needs to be explored for potential beneficial role in COVID-19 in preclinical and clinical studies. We also hypothesise the possibility of drug having anti-inflammatory action in coronavirus associated severe respiratory illness based on few in-vitro and in-vivo reports which however needs to be confirmed clinically.

PMID: 33246694 [PubMed - as supplied by publisher]

Analysis of cellular models of clonal evolution reveals co-evolution of imatinib and HSP90 inhibitor resistances.

Biochem Biophys Res Commun. 2020 Nov 24;:

Authors: Arolla RG, Malladi S, Bhaduri U, Gayatri MB, Pattamshetty P, Mohan V, Katika MR, Madhava Reddy AB, Satyanarayana Rao MR, Vudem DR, Kancha RK

Abstract
Treatment relapse due to clonal evolution was shown to be an independent factor for poor prognosis in advanced stages of chronic myeloid leukemia. Overcoming secondary resistance arising due to clonal evolution is still an unmet need and lack of adequate pre-clinical models hampers the identification of underlying mechanisms and testing of alternate treatment strategies. The current study thus aimed to create cellular models to study molecular mechanisms underlying clonal evolution and identify strategies to overcome the secondary drug resistance. Analysis of cell lines derived from three independent cell-based screens revealed the co-evolution specifically of imatinib and HSP90 inhibitor (HSP90i) resistances despite their exposure to a single inhibitor alone. Molecular and biochemical characterization of these cell lines revealed additional cytogenetic abnormalities, differential activation of pro-survival signaling molecules and over expression of ABL kinase and HSP90 genes. Importantly, all the imatinib-HSP90i dual resistant cell lines remained sensitive to sorafenib and vorinostat suggesting their utility in treating patients who relapse upon imatinib treatment due to clonal evolution. In addition, we cite similar examples of dual resistance towards various kinase inhibitors and HSP90i in some cell lines that represent solid cancers suggesting co-evolution leading to secondary drug resistance as a pan-cancer phenomenon. Taken together, our results suggest the efficacy of HSP90i in overcoming drug resistance caused by point mutations in the target kinase but not in cases of clonal evolution.

PMID: 33246559 [PubMed - as supplied by publisher]

Bioenergetics Impairment of Trypanosoma cruzi by the Antihypertensive Manidipine: A Drug Repurposing Strategy.

Acta Trop. 2020 Nov 24;:105768

Authors: Correa ITS, da Costa-Silva TA, Tempone AG

Abstract
Considering the lack of effective and safe therapy for the treatment of Chagas disease, the antihypertensive drug manidipine (MDP) was in vitro evaluated against Trypanosoma cruzi. The bioenergetics of trypomastigotes was studied in the presence of the drug using fluorimetric and luminescent assays. Manidipine showed a potent antiparasitic activity, with IC50 values of 0.1 μM (intracellular amastigotes) and 3 μM (trypomastigotes), resulting in a promising selectivity index against the amastigotes (>1459). Using fluorimetric analysis, the drug showed depolarisation of the electric potential of the plasma membrane with no alteration of the permeability. A decrease in ATP levels suggested a bioenergetic alteration of the mitochondria, which was confirmed by the depolarisation of the mitochondrial membrane potential and a slight increase of the ROS levels. This is the first study to show the promising in vitro effectiveness of the antihypertensive MDP against T. cruzi, which may represent a candidate for future investigations in animal models.

PMID: 33245907 [PubMed - as supplied by publisher]

Drug Repurposing in Medulloblastoma: Challenges and Recommendations.

Curr Treat Options Oncol. 2020 Nov 27;22(1):6

Authors: Hammoud H, Saker Z, Harati H, Fares Y, Bahmad HF, Nabha S

Abstract
OPINION STATEMENT: Medulloblastoma is the most frequently diagnosed primary malignant brain tumor among children. Currently available therapeutic strategies are based on surgical resection, chemotherapy, and/or radiotherapy. However, majority of patients quickly develop therapeutic resistance and are often left with long-term therapy-related side effects and sequelae. Therefore, there remains a dire need to develop more effective therapeutics to overcome the acquired resistance to currently available therapies. Unfortunately, the process of developing novel anti-neoplastic drugs from bench to bedside is highly time-consuming and very expensive. A wide range of drugs that are already in clinical use for treating non-cancerous diseases might commonly target tumor-associated signaling pathways as well and hence be of interest in treating different cancers. This is referred to as drug repurposing or repositioning. In medulloblastoma, drug repurposing has recently gained a remarkable interest as an alternative therapy to overcome therapy resistance, wherein existing non-tumor drugs are being tested for their potential anti-neoplastic effects outside the scope of their original use.

PMID: 33245404 [PubMed - as supplied by publisher]

Repurposing of well-known medications as antivirals: hydroxychloroquine and chloroquine - from HIV-1 infection to COVID-19.

Expert Rev Anti Infect Ther. 2020 11;18(11):1119-1133

Authors: Naghipour S, Ghodousi M, Rahsepar S, Elyasi S

Abstract
INTRODUCTION: Chloroquine (CQ) and hydroxychloroquine (HCQ) originally were prescribed for prevention or treatment of malaria, but now successfully are used in several rheumatologic diseases. In addition, in recent decades considering their immunomodulatory effects, high tolerably, and low cost, they are evaluated for various viral infections from HIV to COVID-19.
AREAS COVERED: In this review, we tried to summarize all available studies on HCQ and CQ efficacy for management of viral infections and the probable mechanisms of action. The data were collected by searching 'Hydroxychloroquine,' 'Chloroquine,' 'Viral infection,' and names of various viral infections in PubMed/MEDLINE, Scopus, and Google Scholar databases from commencement to June 2020. Out of 95 search results, 74 most relevant works were gathered.
EXPERT OPINION: HCQ/CQ showed acceptable efficacy in HIV especially as an adjuvant treatment beside routine HAART. However, for some viral infections such as ZIKA, EBOLA, SARS-CoV, and MERS-CoV, human studies are lacking. In the COVID-19 pandemic, in vitro and preliminary human studies showed encouraging findings. However, later well-designed trials and retrospective studies with large sample size not only reported non-significant efficacy but also showed more cardiac adverse reactions. Alkalinization of acid vesicles is the most important mechanism of action.

PMID: 32631083 [PubMed - indexed for MEDLINE]