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Drug repurposing

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https://www.readbyqxmd.com/read/29150641/repurposing-of-the-anti-malaria-drug-chloroquine-for-zika-virus-treatment-and-prophylaxis
#1
Sergey A Shiryaev, Pinar Mesci, Antonella Pinto, Isabella Fernandes, Nicholas Sheets, Sujan Shresta, Chen Farhy, Chun-Teng Huang, Alex Y Strongin, Alysson R Muotri, Alexey V Terskikh
One of the major challenges of the current Zika virus (ZIKV) epidemic is to prevent congenital foetal abnormalities, including microcephaly, following ZIKV infection of pregnant women. Given the urgent need for ZIKV prophylaxis and treatment, repurposing of approved drugs appears to be a viable and immediate solution. We demonstrate that the common anti-malaria drug chloroquine (CQ) extends the lifespan of ZIKV-infected interferon signalling-deficient AG129 mice. However, the severity of ZIKV infection in these mice precludes the study of foetal (vertical) viral transmission...
November 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29148875/repurposing-of-kinase-inhibitors-as-broad-spectrum-antiviral-drugs
#2
Stanford Schor, Shirit Einav
The high cost of drug development and the narrow spectrum of coverage typically provided by direct-acting antivirals limit the scalability of this antiviral approach. This review summarizes progress and challenges in the repurposing of approved kinase inhibitors as host-targeted broad-spectrum antiviral therapies.
November 17, 2017: DNA and Cell Biology
https://www.readbyqxmd.com/read/29146245/repurposing-cationic-amphiphilic-drugs-as-adjuvants-to-induce-lysosomal-sirna-escape-in-nanogel-transfected-cells
#3
Freya Joris, Lynn De Backer, Thijs Van de Vyver, Chiara Bastiancich, Stefaan C De Smedt, Koen Raemdonck
Cytosolic delivery remains a major bottleneck for siRNA therapeutics. To facilitate delivery, siRNAs are often enclosed in nanoparticles (NPs). However, upon endocytosis such NPs are mainly trafficked towards lysosomes. To avoid degradation, cytosolic release of siRNA should occur prior to fusion of endosomes with lysosomes, but current endosomal escape strategies remain inefficient. In contrast to this paradigm, we aim to exploit lysosomal accumulation by treating NP-transfected cells with low molecular weight drugs that release the siRNA from the lysosomes into the cytosol...
November 13, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/29143719/microbial-protein-targets-towards-understanding-and-intervention
#4
Paul W Denny
The rise of antimicrobial resistance, coupled with a lack of industrial focus on antimicrobial discovery over preceding decades, has brought the world to a crisis point. With both human and animal health set to decline due to increased disease burdens caused by near untreatable microbial pathogens, there is an urgent need to identify new antimicrobials. Central to this is the elucidation of new, robustly validated, drug targets. Informed by industrial practice and concerns, the use of both biological and chemical tools in validation is key...
November 16, 2017: Parasitology
https://www.readbyqxmd.com/read/29143192/middle-east-respiratory-syndrome-and-severe-acute-respiratory-syndrome-current-therapeutic-options-and-potential-targets-for-novel-therapies
#5
REVIEW
Julie Dyall, Robin Gross, Jason Kindrachuk, Reed F Johnson, Gene G Olinger, Lisa E Hensley, Matthew B Frieman, Peter B Jahrling
No specific antivirals are currently available for two emerging infectious diseases, Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). A literature search was performed covering pathogenesis, clinical features and therapeutics, clinically developed drugs for repurposing and novel drug targets. This review presents current knowledge on the epidemiology, pathogenesis and clinical features of the SARS and MERS coronaviruses. The rationale for and outcomes with treatments used for SARS and MERS is discussed...
November 15, 2017: Drugs
https://www.readbyqxmd.com/read/29142299/the-immunomodulatory-drug-glatiramer-acetate-is-also-an-effective-antimicrobial-agent-that-kills-gram-negative-bacteria
#6
Stig Hill Christiansen, Ronan A Murphy, Kristian Juul-Madsen, Marlene Fredborg, Michael Lykke Hvam, Esben Axelgaard, Sandra M Skovdal, Rikke Louise Meyer, Uffe B Skov Sørensen, Arne Möller, Jens Randel Nyengaard, Niels Nørskov-Lauritsen, Mikala Wang, Mihaela Gadjeva, Kenneth A Howard, Jane C Davies, Eskild Petersen, Thomas Vorup-Jensen
Classic drug development strategies have failed to meet the urgent clinical needs in treating infections with Gram-negative bacteria. Repurposing drugs can lead to timely availability of new antibiotics, accelerated by existing safety profiles. Glatiramer acetate (GA) is a widely used and safe formulation for treatment of multiple sclerosis. It contains a large diversity of essentially isomeric polypeptides with the cationic and amphiphilic character of many antimicrobial peptides (AMP). Here, we report that GA is antibacterial, targeting Gram-negative organisms with higher activity towards Pseudomonas aeruginosa than the naturally-occurring AMP LL-37 in human plasma...
November 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29138369/-metabolic-competition-in-tumor-microenvironment
#7
Shingo Eikawa, Heiichiro Udono
Metabolic pathways tightly regulate T cell response in host defense against infection and cancer. Glycolysis plays a key role in effector T cell differentiation and its function. More recent studies have demonstrated that tumor microenvironment forms hypoxia and metabolic disadvantage of immune cells. These environmental attributions impair the effector T cell survival, proliferation and function. Therefore repurposing of metabolic drugs might develop a novel cancer immunotherapy based on the targeting of T cell immunometabolism...
November 2017: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/29135106/evidence-for-the-efficacy-of-disulfiram-and-copper-combination-in-glioblastoma-multiforme-a-propos-of-a-case
#8
Petros N Karamanakos, Dimitrios T Trafalis, Dionysios J Papachristou, Eleftheria S Panteli, Maria Papavasilopoulou, Andreas Karatzas, Dimitrios Kardamakis, Georgios Nasioulas, Marios Marselos
Glioblastoma multiforme (GBM) is the most common and aggressive malignancy of the central nervous system. Treatment usually involves a combination of surgical resection, chemotherapy, and radiotherapy, but ultimately this condition is incurable. Besides the dismal prognosis of GBM, financial factors have also presented challenges for advancing treatments. Taking into consideration the high cost of developing new anticancer drugs as well as the fact that GBM is a rare disease, thus further limiting financial incentive for drug development, it becomes obvious that there has been growing interest for repurposing candidates...
September 2017: Journal of B.U.ON.: Official Journal of the Balkan Union of Oncology
https://www.readbyqxmd.com/read/29133594/competitive-kinase-enrichment-proteomics-reveals-that-abemaciclib-inhibits-gsk3%C3%AE-and-activates-wnt-signaling
#9
Emily M Cousins, Dennis Goldfarb, Feng Yan, Jose Roques, David B Darr, Gary L Johnson, Michael B Major
The cellular and organismal phenotypic response to a small-molecule kinase inhibitor is defined collectively by the inhibitor's targets and their functions. The selectivity of small-molecule kinase inhibitors is commonly determined in vitro, using purified kinases and substrates. Recently, competitive chemical proteomics has emerged as a complementary, unbiased, cell-based methodology to define the target landscape of kinase inhibitors. Here, we evaluated and optimized a competitive multiplexed inhibitor bead mass spectrometry (MIB/MS) platform using cell lysates, live cells, and treated mice...
November 13, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29133031/chloroquine-upregulates-trail-trailr2-expression-and-potentiates-doxorubicin-anti-tumor-activity-in-thioacetamide-induced-hepatocellular-carcinoma-model
#10
Sahar A Helmy, Mohamed El-Mesery, Amro El-Karef, Laila A Eissa, Amal M El Gayar
Impaired apoptosis and systemic toxicity of chemotherapeutic drugs make cancer treatment suboptimal. Thus, there is urgency for drug repurposing which facilitates discovery of safe and effective combination therapy. This study aimed to evaluate chloroquine's (CQ) ability to trigger TRAIL/TRAILR2 apoptotic pathway in thioacetamide (TAA)-induced hepatocellular carcinoma (HCC) either alone or in combination with doxorubicin (DOX). Moreover, its ability to attenuate DOX-induced cardiotoxicity was investigated. TAA was injected in male Sprague Dawely rats (200 mg/kg; ip; 2 times/week) for 16 weeks...
November 10, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/29131005/a-review-of-anesthetic-effects-on-renal-function-potential-organ-protection
#11
Negar Motayagheni, Sheshanna Phan, Crystal Eshraghi, Ala Nozari, Anthony Atala
BACKGROUND: Renal protection is a critical concept for anesthesiologists, nephrologists, and urologists, since anesthesia and renal function are highly interconnected and can potentially interfere with one another. Therefore, a comprehensive understanding of anesthetic drugs and their effects on renal function remains fundamental to the success of renal surgeries, especially transplant procedures. Some experimental studies have shown that some anesthetics provide protection against renal ischemia/reperfusion (IR) injury, but there is limited clinical evidence...
November 7, 2017: American Journal of Nephrology
https://www.readbyqxmd.com/read/29129046/acebutolol-a-cardioselective-beta-blocker-promotes-glucose-uptake-in-diabetic-model-cells-by-inhibiting-jnk-jip1-interaction
#12
Yi Li, Nan-Young Jung, Jae Cheal Yoo, Yul Kim, Gwan-Su Yi
The phosphorylation of JNK is known to induce insulin resistance in insulin target tissues. The inhibition of JNK-JIP1 interaction, which interferes JNK phosphorylation, becomes a potential target for drug development of type 2 diabetes. To discover the inhibitors of JNK-JIP1 interaction, we screened out 30 candidates from 4320 compound library with In Cell Interaction Trap method. The candidates were further confirmed and narrowed down to five compounds using the FRET method in a model cell. Among those five compounds, Acebutolol showed notable inhibition of JNK phosphorylation and elevation of glucose uptake in diabetic models of adipocyte and liver cell...
November 13, 2017: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/29126136/drugbank-5-0-a-major-update-to-the-drugbank-database-for-2018
#13
David S Wishart, Yannick D Feunang, An C Guo, Elvis J Lo, Ana Marcu, Jason R Grant, Tanvir Sajed, Daniel Johnson, Carin Li, Zinat Sayeeda, Nazanin Assempour, Ithayavani Iynkkaran, Yifeng Liu, Adam Maciejewski, Nicola Gale, Alex Wilson, Lucy Chin, Ryan Cummings, Diana Le, Allison Pon, Craig Knox, Michael Wilson
DrugBank (www.drugbank.ca) is a web-enabled database containing comprehensive molecular information about drugs, their mechanisms, their interactions and their targets. First described in 2006, DrugBank has continued to evolve over the past 12 years in response to marked improvements to web standards and changing needs for drug research and development. This year's update, DrugBank 5.0, represents the most significant upgrade to the database in more than 10 years. In many cases, existing data content has grown by 100% or more over the last update...
November 8, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29121589/pharmacological-targeting-of-gsk-3-and-nrf2-provides-neuroprotection-in-a-preclinical-model-of-tauopathy
#14
Antonio Cuadrado, Sebastian Kügler, Isabel Lastres-Becker
Tauopathies are a group of neurodegenerative disorders where TAU protein is presented as aggregates or is abnormally phosphorylated, leading to alterations of axonal transport, neuronal death and neuroinflammation. Currently, there is no treatment to slow progression of these diseases. Here, we have investigated whether dimethyl fumarate (DMF), an inducer of the transcription factor NRF2, could mitigate tauopathy in a mouse model. The signaling pathways modulated by DMF were also studied in mouse embryonic fibroblast (MEFs) from wild type or KEAP1-deficient mice...
November 6, 2017: Redox Biology
https://www.readbyqxmd.com/read/29111882/depletion-of-tylosin-residues-in-feathers-muscle-and-liver-from-broiler-chickens-after-completion-of-antimicrobial-therapy
#15
Javiera Cornejo, Ekaterina Pokrant, Carolina Carvallo, Aldo Maddaleno, Betty San Martín
Tylosin is one of the most commonly used antimicrobial drugs from the macrolide family and in broiler chickens it is used specially for the treatment of infectious pathologies. The poultry industry produces several by-products, among which feathers account for up to 7 percent of a chicken's live weight, thus they amount to a substantial mass across the whole industry. Feathers have been repurposed as an animal feed ingredient by making them feather meal. Therefore, the presence of high concentrations of residues from antimicrobial drugs in feathers might pose a risk to global public health, due to re-entry of these residues into the food chain...
November 7, 2017: Food Additives & Contaminants. Part A, Chemistry, Analysis, Control, Exposure & Risk Assessment
https://www.readbyqxmd.com/read/29110626/the-rationale-for-repurposing-sildenafil-as-an-adjuvant-to-lung-cancer-treatment
#16
Theodore Keats, Rhonda J Rosengren, John C Ashton
There is now a considerable body of evidence for sildenafil possessing anticancer properties. In this article we argue the case for testing sildenafil as a lung cancer therapy chemoadjuvant. Currently, lung cancer is a disease with insufficient treatment options, with only 20% of patients responding to systemic chemotherapy, and even incremental potential improvements should be explored. We review the literature concerning the biochemical, physiological and metabolic effects on cancer cells by sildenafil alone, and when combined with chemotherapeutic agents...
November 2, 2017: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/29109698/the-emerging-facets-of-non-cancerous-warburg-effect
#17
Alyaa M Abdel-Haleem, Nathan E Lewis, Neema Jamshidi, Katsuhiko Mineta, Xin Gao, Takashi Gojobori
The Warburg effect (WE), or aerobic glycolysis, is commonly recognized as a hallmark of cancer and has been extensively studied for potential anti-cancer therapeutics development. Beyond cancer, the WE plays an important role in many other cell types involved in immunity, angiogenesis, pluripotency, and infection by pathogens (e.g., malaria). Here, we review the WE in non-cancerous context as a "hallmark of rapid proliferation." We observe that the WE operates in rapidly dividing cells in normal and pathological states that are triggered by internal and external cues...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/29109161/combating-multi-drug-resistant-pathogens-with-host-directed-non-antibiotic-therapeutics
#18
Jourdan A Andersson, Jian Sha, Michelle L Kirtley, Emily Reyes, Eric C Fitts, Sara M Dann, Ashok K Chopra
Earlier, we reported that 3 Food and Drug Administration-approved drugs, trifluoperazine (TFP, anti-psychotic), amoxapine (AXPN, anti-depressant), and doxapram (DXP, breathing stimulant), identified from an in vitro murine macrophage cytotoxicity screen, provided 40-60% protection to mice against pneumonic plague when administered at the time of infection for 1-3 days. In this study, the therapeutic potential of these drugs was further evaluated in mice when administered up to 48 h post-infection against pneumonic plague...
November 6, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29107691/antibiotic-bedaquiline-effectively-targets-growth-survival-and-tumor-angiogenesis-of-lung-cancer-through-suppressing-energy-metabolism
#19
Xiaomu Wu, Fajiu Li, Xiaojiang Wang, Chenghong Li, Qinghua Meng, Chuanhai Wang, Jie Huang, Shi Chen, Ziyang Zhu
Tumor angiogenesis plays essential roles during lung cancer progression and metastasis. Therapeutic agent that targets both tumor cell and vascular endothelial cell may achieve additional anti-tumor efficacy. We demonstrate that bedaquiline, a FDA-approved antibiotic drug, effectively targets lung cancer cells and angiogenesis. Bedaquiline dose-dependently inhibits proliferation and induces apoptosis of a panel of lung cancer cell lines regardless of subtypes and molecular heterogeneity. Bedaquiline also inhibits capillary network formation of human lung tumor associated-endothelial cell (HLT-EC) on Matrigel and its multiple functions, such as spreading, proliferation and apoptosis, even in the presence of vascular endothelial growth factor (VEGF)...
October 28, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29099956/recycling-drug-screen-repurposes-hydroxyurea-as-a-sensitizer-of-glioblastomas-to-temozolomide-targeting-de-novo-dna-synthesis-irrespective-of-molecular-subtype
#20
Jian Teng, Seyedali Hejazi, Lotte Hiddingh, Litia Carvalho, Mark de Gooijer, Hiroaki Wakimoto, Marco Barazas, Marie Tannous, Andrew S Chi, David P Noske, Pieter Wesseling, Thomas Wurdinger, Tracy T Batchelor, Bakhos A Tannous
Background: Glioblastoma (GBM) is the most common and most aggressive primary malignant brain tumor. Standard-of-care treatment involves maximal surgical resection of the tumor followed by radiation and chemotherapy (temozolomide; TMZ). The five-year survival rate of patients with GBM is <10%, a colossal failure that has been partially attributed to intrinsic and/or acquired resistance to TMZ through MGMT (O6-methylguanine DNA methyltransferase) promoter methylation status in the tumor...
November 1, 2017: Neuro-oncology
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