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Drug repurposing

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https://www.readbyqxmd.com/read/28644007/cyclotides-as-tools-in-chemical-biology
#1
Simon J de Veer, Joachim Weidmann, David J Craik
Among the various molecules that plants produce for defense against pests and pathogens, cyclotides stand out as exceptionally stable and structurally unique. These ribosomally synthesized peptides are around 30 amino acids in size, and are stabilized by a head-to-tail cyclic peptide backbone and three disulfide bonds that form a cystine knot. They occur in certain plants of the Rubiaceae, Violaceae, Cucurbitaceae, Fabaceae, and Solanaceae families, with an individual plant producing up to hundreds of different cyclotides...
June 23, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28643446/artemisinin-as-an-anticancer-drug-recent-advances-in-target-profiling-and-mechanisms-of-action
#2
REVIEW
Yin Kwan Wong, Chengchao Xu, Karunakaran A Kalesh, Yingke He, Qingsong Lin, W S Fred Wong, Han-Ming Shen, Jigang Wang
Artemisinin and its derivatives (collectively termed as artemisinins) are among the most important and effective antimalarial drugs, with proven safety and efficacy in clinical use. Beyond their antimalarial effects, artemisinins have also been shown to possess selective anticancer properties, demonstrating cytotoxic effects against a wide range of cancer types both in vitro and in vivo. These effects appear to be mediated by artemisinin-induced changes in multiple signaling pathways, interfering simultaneously with multiple hallmarks of cancer...
June 23, 2017: Medicinal Research Reviews
https://www.readbyqxmd.com/read/28643372/fine-tuning-perk-signaling-for-neuroprotection
#3
REVIEW
Mark Halliday, Daniel Hughes, Giovanna Mallucci
Protein translation and folding are tightly controlled processes in all cells, by proteostasis, an important component of which is the unfolded protein response (UPR). During periods of endoplasmic reticulum stress due to protein misfolding, the UPR activates a coordinated response in which the PERK branch activation restricts translation, while a variety of genes involved with protein folding, degradation, chaperone expression and stress responses are induced through signaling of the other branches. Chronic overactivation of the UPR, particularly the PERK branch is observed in the brains of patients in a number of protein misfolding neurodegenerative diseases, including Alzheimer's, and Parkinson's diseases and the taopathies...
June 23, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28643328/drug-repurposing-by-simulating-flow-through-protein-protein-interaction-networks
#4
M Manczinger, V Bodnár, B T Papp, B Sz Bolla, K Szabó, B Balázs, E Csányi, E Szél, G Erős, L Kemény
As drug development is extremely expensive, the identification of novel indications for in-market drugs is financially attractive. Multiple algorithms are used to support such drug repurposing, but highly reliable methods combining simulation of intracellular networks and machine learning are currently not available. We developed an algorithm that simulates drug effects on the flow of information through protein-protein interaction networks, and uses Support Vector Machine to identify potentially effective drugs in our model disease, psoriasis...
June 23, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28641310/potentiating-the-effects-of-radiotherapy-in-rectal-cancer-the-role-of-aspirin-statins-and-metformin-as-adjuncts-to-therapy
#5
K J Gash, A C Chambers, D E Cotton, A C Williams, M G Thomas
BACKGROUND: Complete tumour response (pCR) to neo-adjuvant chemo-radiotherapy for rectal cancer is associated with a reduction in local recurrence and improved disease-free and overall survival, but is achieved in only 20-30% of patients. Drug repurposing for anti-cancer treatments is gaining momentum, but the potential of such drugs as adjuncts, to increase tumour response to chemo-radiotherapy in rectal cancer, is only just beginning to be recognised. METHODS: A systematic literature search was conducted and all studies investigating the use of drugs to enhance response to neo-adjuvant radiation in rectal cancer were included...
June 22, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28636189/discovery-of-alkyl-bis-oxy-dibenzimidamide-derivatives-as-novel-protein-arginine-methyltransferase-1-prmt1-inhibitors
#6
Wei-Yao Zhang, Wen-Chao Lu, Hao Jiang, Zheng-Bing Lv, Yi-Qian Xie, Fu-Lin Lian, Zhong-Jie Liang, Yu-Xi Jiang, Da-Jin Wang, Cheng Luo, Jia Jin, Fei Ye
Protein arginine methylation, a post-translational modification critical for a variety of biological processes, is catalyzed by protein arginine N-methyltransferases (PRMTs). In particular, PRMT1 is responsible for over 85% of the arginine methylation in mammalian cells. Dysregulation of PRMT1 is involved in diverse pathological diseases including cancers. However, most current PRMT1inhibitors are lack of specificity, efficacy, and bioavailability. Herein, a series of alkyl bis(oxy)dibenzimidamide derivatives were identified as selective PRMT1 inhibitors...
June 21, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28628632/increasing-procaspase-8-expression-using-repurposed-drugs-to-induce-hiv-infected-cell-death-in-ex-vivo-patient-cells
#7
Rahul Sampath, Nathan W Cummins, Sekar Natesampillai, Gary D Bren, Thomas D Chung, Jason Baker, Keith Henry, Amélie Pagliuzza, Andrew D Badley
HIV persists because a reservoir of latently infected CD4 T cells do not express viral proteins and are indistinguishable from uninfected cells. One approach to HIV cure suggests that reactivating HIV will activate cytotoxic pathways; yet when tested in vivo, reactivating cells do not die sufficiently to reduce cell-associated HIV DNA levels. We recently showed that following reactivation from latency, HIV infected cells generate the HIV specific cytotoxic protein Casp8p41 which is produced by HIV protease cleaving procaspase 8...
2017: PloS One
https://www.readbyqxmd.com/read/28624878/a-combination-of-three-repurposed-drugs-administered-at-reperfusion-as-a-promising-therapy-for-postischemic-brain-injury
#8
I-Chen Yu, Ping-Chang Kuo, Jui-Hung Yen, Hallel C Paraiso, Eric T Curfman, Benecia C Hong-Goka, Robert D Sweazey, Fen-Lei Chang
Cerebral ischemia leads to multifaceted injury to the brain. A polytherapeutic drug that can be administered immediately after reperfusion may increase protection to the brain by simultaneously targeting multiple deleterious cascades. This study evaluated efficacy of the combination of three clinically approved drugs: lamotrigine, minocycline, and lovastatin, using two mouse models: global and focal cerebral ischemia induced by transient occlusion of the common carotid arteries or the middle cerebral artery, respectively...
June 17, 2017: Translational Stroke Research
https://www.readbyqxmd.com/read/28621668/blocking-epithelial-to-mesenchymal-transition-in-glioblastoma-with-a-sextet-of-repurposed-drugs-the-eis-regimen
#9
Richard E Kast, Nicolas Skuli, Georg Karpel-Massler, Guido Frosina, Timothy Ryken, Marc-Eric Halatsch
This paper outlines a treatment protocol to run alongside of standard current treatment of glioblastoma- resection, temozolomide and radiation. The epithelial to mesenchymal transition (EMT) inhibiting sextet, EIS Regimen, uses the ancillary attributes of six older medicines to impede EMT during glioblastoma. EMT is an actively motile, therapy-resisting, low proliferation, transient state that is an integral feature of cancers' lethality generally and of glioblastoma specifically. It is believed to be during the EMT state that glioblastoma's centrifugal migration occurs...
June 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28620943/drug-repurposing-for-aging-research-using-model-organisms
#10
Matthias Ziehm, Satwant Kaur, Dobril K Ivanov, Pedro J Ballester, David Marcus, Linda Partridge, Janet M Thornton
Many increasingly prevalent diseases share a common risk factor: age. However, little is known about pharmaceutical interventions against aging, despite many genes and pathways shown to be important in the aging process and numerous studies demonstrating that genetic interventions can lead to a healthier aging phenotype. An important challenge is to assess the potential to repurpose existing drugs for initial testing on model organisms, where such experiments are possible. To this end, we present a new approach to rank drug-like compounds with known mammalian targets according to their likelihood to modulate aging in the invertebrates Caenorhabditis elegans and Drosophila...
June 16, 2017: Aging Cell
https://www.readbyqxmd.com/read/28617219/drug-repositioning-for-enzyme-modulator-based-on-human-metabolite-likeness
#11
Yoon Hyeok Lee, Hojae Choi, Seongyong Park, Boah Lee, Gwan-Su Yi
BACKGROUND: Recently, the metabolite-likeness of the drug space has emerged and has opened a new possibility for exploring human metabolite-like candidates in drug discovery. However, the applicability of metabolite-likeness in drug discovery has been largely unexplored. Moreover, there are no reports on its applications for the repositioning of drugs to possible enzyme modulators, although enzyme-drug relations could be directly inferred from the similarity relationships between enzyme's metabolites and drugs...
May 31, 2017: BMC Bioinformatics
https://www.readbyqxmd.com/read/28617137/drugs-currently-under-investigation-for-the-treatment-of-invasive-candidiasis
#12
Matthew W McCarthy, Thomas J Walsh
The widespread implementation of immunosuppressants, immunomodulators, hematopoietic stem cell transplantation and solid organ transplantation in clinical practice has led to an expanding population of patients who are at risk for invasive candidiasis, which is the most common form of fungal disease among hospitalized patients in the developed world. The emergence of drug-resistant Candida spp. has added to the morbidity associated with invasive candidiasis and novel therapeutic strategies are urgently needed...
June 15, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28615941/development-and-optimization-of-an-injectable-formulation-of-copper-diethyldithiocarbamate-an-active-anticancer-agent
#13
Mohamed Wehbe, Malathi Anantha, Minghan Shi, Ada Wai-Yin Leung, Wieslawa H Dragowska, Léon Sanche, Marcel B Bally
Copper diethyldithiocarbamate (Cu(DDC)2) is the active anticancer agent generated when disulfiram (DSF) is provided in the presence of copper. To date, research directed toward repurposing DSF as an anticancer drug has focused on administration of DSF and copper in combination, efforts that have proven unsuccessful in clinical trials. This is likely due to the inability to form Cu(DDC)2 at relevant concentrations in regions of tumor growth. Little effort has been directed toward the development of Cu(DDC)2 because of the inherent aqueous insolubility of the complex...
2017: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/28615299/ormeloxifene-suppresses-prostate-tumor-growth-and-metastatic-phenotypes-via-inhibition-of-oncogenic-%C3%AE-catenin-signaling-and-emt-progression
#14
Bilal Bin Hafeez, Aditya Ganju, Mohammed Sikander, Vivek K Kashyap, Zubair Bin Hafeez, Neeraj Chauhan, Shabnam Malik, Andrew E Massey, Manish K Tripathi, Fathi T Halaweish, Nadeem Zafar, Man M Singh, Murali M Yallapu, Meena Jaggi, Subhash C Chauhan
Ormeloxifene (ORM), is a clinically approved selective estrogen receptor modulator, which has also shown excellent anti-cancer activity, thus it can be an ideal repurposing pharmacophore. Herein, we report therapeutic effects of ORM on prostate cancer (PrCa) and elucidate a novel molecular mechanism of its anti-cancer activity. ORM treatment inhibited epithelial to mesenchymal transition (EMT) process as evident by repression of N-cadherin, Slug, Snail, and vimentin, MMPs (MMP2 and MMP3), β-catenin/TCF-4 transcriptional activity, and induced the expression of pGSK3β...
June 14, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28608171/genetic-approaches-to-understanding-psychiatric-disease
#15
REVIEW
Jacob J Michaelson
Human genetic studies have been the driving force in bringing to light the underlying biology of psychiatric conditions. As these studies fill in the gaps in our knowledge of the mechanisms at play, we will be better equipped to design therapies in rational and targeted ways, or repurpose existing therapies in previously unanticipated ways. This review is intended for those unfamiliar with psychiatric genetics as a field and provides a primer on different modes of genetic variation, the technologies currently used to probe them, and concepts that provide context for interpreting the gene-phenotype relationship...
June 12, 2017: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
https://www.readbyqxmd.com/read/28606994/calcineurin-nfat-signalling-in-myeloid-leucocytes-new-prospects-and-pitfalls-in-immunosuppressive-therapy
#16
REVIEW
Kamila Bendickova, Federico Tidu, Jan Fric
Myeloid leucocytes mediate host protection against infection and critically regulate inflammatory responses in body tissues. Pattern recognition receptor signalling is crucial for myeloid cell responses to pathogens, but growing evidence suggests an equally potent role for Calcineurin-NFAT signalling in control of myeloid cell function. All major subsets of myeloid leucocytes employ Calcineurin-NFAT signalling during immune responses to pathogens and/or tissue damage, but the influence this pathway exerts on pathogen clearance and host susceptibility to infection is not fully understood...
June 12, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28603644/neighbours-of-cancer-related-proteins-have-key-influence-on-pathogenesis-and-could-increase-the-drug-target-space-for-anticancer-therapies
#17
Dezső Módos, Krishna C Bulusu, Dávid Fazekas, János Kubisch, Johanne Brooks, István Marczell, Péter M Szabó, Tibor Vellai, Péter Csermely, Katalin Lenti, Andreas Bender, Tamás Korcsmáros
Even targeted chemotherapies against solid cancers show a moderate success increasing the need to novel targeting strategies. To address this problem, we designed a systems-level approach investigating the neighbourhood of mutated or differentially expressed cancer-related proteins in four major solid cancers (colon, breast, liver and lung). Using signalling and protein-protein interaction network resources integrated with mutational and expression datasets, we analysed the properties of the direct and indirect interactors (first and second neighbours) of cancer-related proteins, not found previously related to the given cancer type...
January 24, 2017: NPJ Systems Biology and Applications
https://www.readbyqxmd.com/read/28601826/study-protocol-of-a-phase-ib-ii-clinical-trial-of-metformin-and-chloroquine-in-patients-with-idh1-mutated-or-idh2-mutated-solid-tumours
#18
Remco J Molenaar, Robert Js Coelen, Mohammed Khurshed, Eva Roos, Matthan Wa Caan, Myra E van Linde, Mathilde Kouwenhoven, Jos Am Bramer, Judith Vmg Bovée, Ron A Mathôt, Heinz-Josef Klümpen, Hanneke Wm van Laarhoven, Cornelis Jf van Noorden, W Peter Vandertop, Hans Gelderblom, Thomas M van Gulik, Johanna W Wilmink
INTRODUCTION: High-grade chondrosarcoma, high-grade glioma and intrahepatic cholangiocarcinoma are aggressive types of cancer with a dismal outcome. This is due to the lack of effective treatment options, emphasising the need for novel therapies. Mutations in the genes IDH1 and IDH2 (isocitrate dehydrogenase 1 and 2) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. IDH1/2-mutated cancer cells produce the oncometabolite D-2-hydroxyglutarate (D-2HG) and are metabolically vulnerable to treatment with the oral antidiabetic metformin and the oral antimalarial drug chloroquine...
June 10, 2017: BMJ Open
https://www.readbyqxmd.com/read/28596306/mendelian-randomisation-in-cardiovascular-research-an-introduction-for-clinicians
#19
REVIEW
Derrick A Bennett, Michael V Holmes
Understanding the causal role of biomarkers in cardiovascular and other diseases is crucial in order to find effective approaches (including pharmacological therapies) for disease treatment and prevention. Classical observational studies provide naïve estimates of the likely role of biomarkers in disease development; however, such studies are prone to bias. This has direct relevance for drug development as if drug targets track to non-causal biomarkers, this can lead to expensive failure of these drugs in phase III randomised controlled trials...
June 8, 2017: Heart: Official Journal of the British Cardiac Society
https://www.readbyqxmd.com/read/28595531/repurposed-drugs-as-potential-therapeutic-candidates-for-management-of-alzheimer-s-disease
#20
Muhammad Shoaib, Mohammad A Kamal, Syed Mohd Danish Rizvi
Drug repurposing is an innovative approach as it provides fresh implications to previously approved and established drug compounds. Due to high failure rates and cost involved in the drug development process, many pharmaceutical companies are primarily focusing on drug repurposing strategy. In Alzheimer disease, existing therapeutic agents only provide symptomatic benefits and does not get involved in disease modification, therefore, the alternative approach of repurposing could be applied to inhibit neurodegeneracy process and other pathological complications...
June 6, 2017: Current Drug Metabolism
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