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Trends in Pharmacological Sciences

Yoshinori Moriyama, Masatoshi Nomura
Clodronate is a first-generation bisphosphonate used worldwide for antiresorptive therapy for osteoporosis. Although clodronate is analgesic in nature, its mechanism and efficacy were unknown for some time. Recently, clodronate was identified as a selective and potent inhibitor for vesicular nucleotide transporter (VNUT), a transporter responsible for vesicular storage of ATP. Clodronate inhibits vesicular ATP release from neurons and reduces chronic neuropathic and inflammatory pain following blockade of purinergic chemical transmission...
November 13, 2017: Trends in Pharmacological Sciences
Leigh A Stoddart, Laura E Kilpatrick, Stephen J Hill
Recent advances in the development of fluorescent ligands for G-protein-coupled receptors (GPCRs) and receptor tyrosine kinase receptors (RTKs) have facilitated the study of these receptors in living cells. A limitation of these ligands is potential uptake into cells and increased nonspecific binding. However, this can largely be overcome by using proximity approaches, such as bioluminescence resonance energy transfer (BRET), which localise the signal (within 10nm) to the specific receptor target. The recent engineering of NanoLuc has resulted in a luciferase variant that is smaller and significantly brighter (up to tenfold) than existing variants...
November 10, 2017: Trends in Pharmacological Sciences
Igor V Kurochkin, Enrico Guarnera, Igor N Berezovsky
After decades of research and clinical trials there is still no cure for Alzheimer's disease (AD). While impaired clearance of amyloid beta (Aβ) peptides is considered as one of the major causes of AD, it was recently complemented by a potential role of other toxic amyloidogenic species. Insulin-degrading enzyme (IDE) is the proteolytic culprit of various β-forming peptides, both extracellular and intracellular. On the basis of demonstrated allosteric activation of IDE against Aβ, it is possible to propose a new strategy for the targeted IDE-based cleansing of different toxic aggregation-prone peptides...
November 10, 2017: Trends in Pharmacological Sciences
James H Felce, Simon J Davis, David Klenerman
How G protein-coupled receptors (GPCRs) are organized at the cell surface remains highly contentious. Single-molecule (SM) imaging is starting to inform this debate as receptor behavior can now be visualized directly, without the need for interpreting ensemble data. The limited number of SM studies of GPCRs undertaken to date have strongly suggested that dimerization is at most transient, and that most receptors are monomeric at any given time. However, even SM data has its caveats and needs to be interpreted carefully...
November 6, 2017: Trends in Pharmacological Sciences
Ago Rinken, Darja Lavogina, Sergei Kopanchuk
Binding of fluorescent ligands (tracers) to their target receptors can be directly monitored over time, as the binding of a low-molecular-weight (LMW) tracer to a larger particle causes an increase of fluorescence anisotropy (FA). The combination of bright fluorophores, tracers with low nonspecific binding, and budded baculovirus particles (BVPs) for overexpression of G protein-coupled receptors (GPCRs) ensures a high signal-to-noise ratio in FA assays. The obtained data enable quantitative assessment of equilibrium binding and kinetic parameters for both the tracer and competing compounds as well as an estimation of the receptor concentration...
November 1, 2017: Trends in Pharmacological Sciences
Ke Chen, Hao Ye, Xiao-Jie Lu, Beicheng Sun, Qi Liu
Cancer immunotherapy with immune-checkpoint blockade (ICB) is considered a promising strategy for cancer treatment. Identifying predictive biomarkers and developing efficient computational models to predict the ICB response are important issues for successful immunotherapy. Here, we present a concise and intuitive survey of the computational issues for ICB response prediction, providing a summary of the available predictive biomarkers and building of one-stop machine-learning models that integrate biomarkers calculable from high-throughput sequencing (HTS) data...
October 28, 2017: Trends in Pharmacological Sciences
Leonard A Levin, Francine Behar-Cohen
The pharmaceutical industry has long known that ∼80% of the results of academic laboratories cannot be reproduced when repeated in industry laboratories. Yet academic investigators are typically unaware of this problem, which severely impedes the drug development process. This academic-industrial complication is not one of deception, but rather a complex issue related to how scientific research is carried out and translated in strikingly different enterprises. This Opinion describes the reasons for inconsistencies between academic and industrial laboratories and what can be done to repair this failure of translation...
October 27, 2017: Trends in Pharmacological Sciences
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October 26, 2017: Trends in Pharmacological Sciences
Manuel Grundmann, Evi Kostenis
Evidence suggests that cells can time-encode signals for secure transport and perception of information, and it appears that this dynamic signaling is a common principle of nature to code information in time. G-protein-coupled receptor (GPCR) signaling networks are no exception as their composition and signal transduction appear temporally flexible. In this review, we discuss the potential mechanisms by which GPCRs code biological information in time to create 'temporal bias.' We highlight dynamic signaling patterns from the second messenger to the receptor-ligand level and shed light on the dynamics of G-protein cycles, the kinetics of ligand-receptor interaction, and the occurrence of distinct signaling waves within the cell...
October 23, 2017: Trends in Pharmacological Sciences
Vinod Kumar, Virender Kumar, Timothy McGuire, Donald W Coulter, John G Sharp, Ram I Mahato
Medulloblastoma (MB) is the most common childhood brain tumor, which occurs in the posterior fossa. MB tumors are highly heterogeneous and have diverse genetic make-ups, with differential microRNA (miRNA) expression profiles and variable prognoses. MB can be classified into four subgroups, each with different origins, pathogenesis, and potential therapeutic targets. miRNA and small-molecule targeted therapies have emerged as a potential new therapeutic paradigm in MB treatment. However, the development of chemoresistance due to surviving cancer stem cells and dysregulation of miRNAs remains a challenge...
October 20, 2017: Trends in Pharmacological Sciences
Michelle L Halls, Meritxell Canals
Genetically encoded Förster resonance energy transfer (FRET) biosensors have been instrumental to our understanding of how intracellular signalling is organised and regulated within cells. In the last decade, the toolbox, dynamic range and applications of these sensors have expanded beyond basic cell biology applications. In particular, FRET biosensors have shed light onto the mechanisms that control the intracellular organisation of G protein-coupled receptor (GPCR) signalling and have allowed the visualisation of signalling events with unprecedented temporal and spatial resolution...
October 17, 2017: Trends in Pharmacological Sciences
Tarun M Kapoor, Rand M Miller
Identifying the direct physiological targets of drugs and chemical probes remains challenging. Here we describe how resistance can be used to achieve 'gold-standard' validation of a chemical inhibitor's direct target in human cells. This involves demonstrating that a silent mutation in the target that suppresses inhibitor activity in cell-based assays can also reduce inhibitor potency in biochemical assays. Further, phenotypes due to target inhibition can be identified as those observed in the inhibitor-sensitive cells, across a range of inhibitor concentrations, but not in genetically matched cells with a silent resistance-conferring mutation in the target...
October 13, 2017: Trends in Pharmacological Sciences
John D Pediani, Richard J Ward, Sara Marsango, Graeme Milligan
Spatial intensity distribution analysis (SpIDA) is a recently developed approach for determining quaternary structure information on fluorophore-labelled proteins of interest in situ. It can be applied to live or fixed cells and native tissue. Using confocal images, SpIDA generates fluorescence intensity histograms that are analysed by super-Poissonian distribution functions to obtain density and quantal brightness values of the fluorophore-labelled protein of interest. This allows both expression level and oligomerisation state of the protein to be determined...
October 9, 2017: Trends in Pharmacological Sciences
Aurora S Blucher, Gabrielle Choonoo, Molly Kulesz-Martin, Guanming Wu, Shannon K McWeeney
A core tenet of precision oncology is the rational choice of drugs to interact with patient-specific biological targets of interest, but it is currently difficult for researchers to obtain consistent and well-supported target information for pharmaceutical drugs. We review current drug-target interaction resources and critically assess how supporting evidence is handled. We introduce the concept of a unified Cancer Targetome to aggregate drug-target interactions in an evidence-based framework. We discuss current unmet needs and the implications for evidence-based clinical omics...
September 27, 2017: Trends in Pharmacological Sciences
Evan J Kyzar, Charles D Nichols, Raul R Gainetdinov, David E Nichols, Allan V Kalueff
Psychedelic drugs, such as lysergic acid diethylamide (LSD), mescaline, and psilocybin, exert profound effects on brain and behavior. After decades of difficulties in studying these compounds, psychedelics are again being tested as potential treatments for intractable biomedical disorders. Preclinical research of psychedelics complements human neuroimaging studies and pilot clinical trials, suggesting these compounds as promising treatments for addiction, depression, anxiety, and other conditions. However, many questions regarding the mechanisms of action, safety, and efficacy of psychedelics remain...
November 2017: Trends in Pharmacological Sciences
H C Stephen Chan, Dillon McCarthy, Jianing Li, Krzysztof Palczewski, Shuguang Yuan
Pain is both a major clinical and economic problem, affecting more people than diabetes, heart disease, and cancer combined. While a variety of prescribed or over-the-counter (OTC) medications are available for pain management, opioid medications, especially those acting on the μ-opioid receptor (μOR) and related pathways, have proven to be the most effective, despite some serious side effects including respiration depression, pruritus, dependence, and constipation. It is therefore imperative that both academia and industry develop novel μOR analgesics which retain their opioid analgesic properties but with fewer or no adverse effects...
November 2017: Trends in Pharmacological Sciences
Bice Chini, Matthijs Verhage, Valery Grinevich
The hypothalamic neuropeptide oxytocin (OT) has attracted the attention both of the scientific community and a general audience because of its prosocial effects in mammals, and OT is now seen as a facilitator of mammalian species propagation. Furthermore, OT is a candidate for the treatment of social deficits in several neuropsychiatric and neurodevelopmental conditions. Despite such possibilities and a long history of studies on OT behavioral effects, the mechanisms of OT actions in the brain remain poorly understood...
November 2017: Trends in Pharmacological Sciences
Xin-Yi Chu, Ye-Mao Liu, Hong-Yu Zhang
Activating nuclear factor erythroid 2 (NF-E2)-related factor (Nrf2) is a widely recognized strategy for combating oxidative-stress-induced diseases. However, Nrf2 activation does not always bring advantageous effects. Therefore, before performing Nrf2-targeted therapy, we must pinpoint whether Nrf2 should be activated or inhibited.
November 2017: Trends in Pharmacological Sciences
A Claudio Cuello
In 1990 it was reported that individuals receiving NSAIDs (non-steroidal anti-inflammatory drugs) showed a markedly reduced prevalence of Alzheimer's disease (AD) compared to the overall population. Large epidemiological studies corroborated this assertion and provoked numerous prospective AD clinical trials with a variety of NSAIDs, all of which demonstrated lack of efficacy. It is postulated that the explanation for the success of NSAIDS in preventing AD onset when given at preclinical stages, and for their failure when administered after AD clinical presentation, lies in the changing nature of central nervous system (CNS) inflammation in the decades-long continuum of AD pathology...
November 2017: Trends in Pharmacological Sciences
Benjamin E Tourdot, Michael Holinstat
Platelets are key contributors to the formation of occlusive thrombi; the major underlying cause of ischemic heart disease and stroke. Antiplatelet therapy has reduced the morbidity and mortality associated with thrombotic events; however, the utility of current antiplatelet therapies is limited by the concomitant risk of an adverse bleeding event. Novel antiplatelet therapies that are more efficacious at inhibiting thrombosis while minimally affecting hemostasis are required. Platelet-type 12-(S)-lipoxygenase (12-LOX), an oxygenase shown to potentiate platelet activation, represents a novel antiplatelet target...
November 2017: Trends in Pharmacological Sciences
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