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  • Opioid and Psychostimulant Plasticity: Targeting Overlap in Nucleus Accumbens Glutamate Signaling
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2018-01-12
    Matthew Hearing, Nicholas Graziane, Yan Dong, Mark J. Thomas

    Commonalities in addictive behavior, such as craving, stimuli-driven drug seeking, and a high propensity for relapse following abstinence, have pushed for a unified theory of addiction that encompasses most abused substances. This unitary theory has recently been challenged – citing distinctions in structural neural plasticity, biochemical signaling, and neural circuitry to argue that addiction to opioids and psychostimulants is behaviorally and neurobiologically distinct. Recent more selective examination of drug-induced plasticity has highlighted that these two drug classes promote an overall reward circuitry signaling overlap through modifying excitatory synapses in the nucleus accumbens – a key constituent of the reward system. We discuss adaptations in presynaptic/postsynaptic and extrasynaptic glutamate signaling produced by opioids and psychostimulants, and their relevance to circuit remodeling and addiction-related behavior – arguing that these core neural adaptations are important targets for developing pharmacotherapies to treat addiction to multiple drugs.

  • Regulatory Science – An Underappreciated Component of Translational Research
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2018-01-09
    Rodney Rouse, Issam Zineh, David G. Strauss

    Translational science refers to translating basic scientific findings to practical application (i.e., ‘bench-to-bedside’). An underappreciated aspect of translational science is regulatory science. Herein, we focus on the importance of regulatory science to facilitate development of innovative new drugs and optimize use of approved drugs, with a call for community participation.

  • Clinical Success of Drug Targets Prospectively Predicted by In Silico Study
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-12-30
    Feng Zhu, Xiao Xu Li, Sheng Yong Yang, Yu Zong Chen

    The selection of the right drug targets is critically important for the successful and cost-effective development and clinical testing of drugs. A 2009 paper reported an in silico prospective prediction of the clinical potential of 156 targets of clinical trial drugs (all of these targets were without an approved drug at the time of the paper’s publication). Eight years later, the assessment of the clinical status of these targets revealed impressive capability of the in silico method in prospectively predicting the clinical success of drug targets.

  • cAMP: From Long-Range Second Messenger to Nanodomain Signalling
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-12-27
    Nshunge Musheshe, Martina Schmidt, Manuela Zaccolo

    How cAMP generates hormone-specific effects has been debated for many decades. Fluorescence resonance energy transfer (FRET)-based sensors for cAMP allow real-time imaging of the second messenger in intact cells with high spatiotemporal resolution. This technology has made it possible to directly demonstrate that cAMP signals are compartmentalised. The details of such signal compartmentalisation are still being uncovered, and recent findings reveal a previously unsuspected submicroscopic heterogeneity of intracellular cAMP. A model is emerging where specificity depends on compartmentalisation and where the physiologically relevant signals are those that occur within confined nanodomains, rather than bulk changes in cytosolic cAMP. These findings subvert the classical notion of cAMP signalling and provide a new framework for the development of targeted therapeutic approaches.

  • Studying GPCR Pharmacology in Membrane Microdomains: Fluorescence Correlation Spectroscopy Comes of Age
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-12-22
    Stephen J. Briddon, Laura E. Kilpatrick, Stephen J. Hill

    G protein-coupled receptors (GPCRs) are organised within the cell membrane into highly ordered macromolecular complexes along with other receptors and signalling proteins. Understanding how heterogeneity in these complexes affects the pharmacology and functional response of these receptors is crucial for developing new and more selective ligands. Fluorescence correlation spectroscopy (FCS) and related techniques such as photon counting histogram (PCH) analysis and image-based FCS can be used to interrogate the properties of GPCRs in these membrane microdomains, as well as their interaction with fluorescent ligands. FCS analyses fluorescence fluctuations within a small-defined excitation volume to yield information about their movement, concentration and molecular brightness (aggregation). These techniques can be used on live cells with single-molecule sensitivity and high spatial resolution. Once the preserve of specialist equipment, FCS techniques can now be applied using standard confocal microscopes. This review describes how FCS and related techniques have revealed novel insights into GPCR biology.

  • Targeting the IDO1/TDO2–KYN–AhR Pathway for Cancer Immunotherapy – Challenges and Opportunities
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-12-15
    Jae Eun Cheong, Lijun Sun

    Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) catalyze the commitment step of the kynurenine (KYN) metabolic pathway. Traditionally the immunosuppressive effect of IDO1 has been attributed mainly to reduced levels of tryptophan, which activates the kinase general control nonderepressible 2 (GCN2). Emerging data have shed light on an unexpected role of the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) in transducing the tumor immune escape function imparted by IDO1 and TDO2. AhR activation by the IDO1/TDO2 product KYN leads to the generation of immune-tolerant dendritic cells (DCs) and regulatory T cells, which collectively foster a tumor immunological microenvironment that is defective in recognizing and eradicating cancer cells. Multiple IDO1 inhibitors have been evaluated in clinical trials. There are novel modalities downstream of IDO1/TDO2 for pharmacological interventions. We review recent progress and future perspectives in targeting the IDO1/TDO2–KYN–AhR signaling pathway for the development of novel cancer immunotherapies.

  • Modernizing Human Cancer Risk Assessment of Therapeutics
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-12-11
    Mark R. Fielden, Lucas D. Ward, Sheroy Minocherhomji, Paul Nioi, Herve Lebrec, David Jacobson-Kram

    Cancer risk assessment of therapeutics is plagued by poor translatability of rodent models of carcinogenesis. In order to overcome this fundamental limitation, new approaches are needed that enable us to evaluate cancer risk directly in humans and human-based cellular models. Our enhanced understanding of the mechanisms of carcinogenesis and the influence of human genome sequence variation on cancer risk motivates us to re-evaluate how we assess the carcinogenic risk of therapeutics. This review will highlight new opportunities for applying this knowledge to the development of a battery of human-based in vitro models and biomarkers for assessing cancer risk of novel therapeutics.

  • Combination Therapies Targeting HDAC and IKK in Solid Tumors
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-12-09
    Ivana Vancurova, Mohammad M. Uddin, Yue Zou, Ales Vancura

    The rationale for developing histone deacetylase (HDAC) inhibitors (HDACi) as anticancer agents was based on their ability to induce apoptosis and cell cycle arrest in cancer cells. However, while HDACi have been remarkably effective in the treatment of hematological malignancies, clinical studies with HDACi as single agents in solid cancers have been disappointing. Recent studies have shown that, in addition to inducing apoptosis in cancer cells, class I HDACi induce IκB kinase (IKK)-dependent expression of proinflammatory chemokines, such as interleukin-8 (IL8; CXCL8), resulting in the increased proliferation of tumor cells, and limiting the effectiveness of HDACi in solid tumors. Here, we discuss the mechanisms responsible for HDACi-induced CXCL8 expression, and opportunities for combination therapies targeting HDACs and IKK in solid tumors.

  • Cancer Radiosensitizers
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-12-07
    Hao Wang, Xiaoyu Mu, Hua He, Xiao-Dong Zhang

    Radiotherapy (RT) is a mainstay treatment for many types of cancer, although it is still a large challenge to enhance radiation damage to tumor tissue and reduce side effects to healthy tissue. Radiosensitizers are promising agents that enhance injury to tumor tissue by accelerating DNA damage and producing free radicals. Several strategies have been exploited to develop highly effective and low-toxicity radiosensitizers. In this review, we highlight recent progress on radiosensitizers, including small molecules, macromolecules, and nanomaterials. First, small molecules are reviewed based on free radicals, pseudosubstrates, and other mechanisms. Second, nanomaterials, such as nanometallic materials, especially gold-based materials that have flexible surface engineering and favorable kinetic properties, have emerged as promising radiosensitizers. Finally, emerging macromolecules have shown significant advantages in RT because these molecules can be combined with biological therapy as well as drug delivery. Further research on the mechanisms of radioresistance and multidisciplinary approaches will accelerate the development of radiosensitizers.

  • Structural Mapping of Adenosine Receptor Mutations: Ligand Binding and Signaling Mechanisms
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-12-05
    Willem Jespers, Anke C. Schiedel, Laura H. Heitman, Robert M. Cooke, Lisa Kleene, Gerard J.P. van Westen, David E. Gloriam, Christa E. Müller, Eddy Sotelo, Hugo Gutiérrez-de-Terán

    The four adenosine receptors (ARs), A1, A2A, A2B, and A3, constitute a subfamily of G protein-coupled receptors (GPCRs) with exceptional foundations for structure-based ligand design. The vast amount of mutagenesis data, accumulated in the literature since the 1990s, has been recently supplemented with structural information, currently consisting of several inactive and active structures of the A2A and inactive conformations of the A1 ARs. We provide the first integrated view of the pharmacological, biochemical, and structural data available for this receptor family, by mapping onto the relevant crystal structures all site-directed mutagenesis data, curated and deposited at the GPCR database (available through http://www.gpcrdb.org). This analysis provides novel insights into ligand binding, allosteric modulation, and signaling of the AR family.

  • Intramolecular and Intermolecular FRET Sensors for GPCRs – Monitoring Conformational Changes and Beyond
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-11-25
    Michael Kauk, Carsten Hoffmann

    Within the past decade, a large increase in structural knowledge from crystallographic studies has significantly fostered our understanding of the structural biology of G protein-coupled receptors (GPCRs). However, information on dynamic events upon receptor activation or deactivation is not yet readily accessed by these structural approaches. GPCR-based fluorescence resonance energy transfer or bioluminescence resonance energy transfer sensors or sensors for interacting proteins (e.g., G proteins or arrestins) can in part cover this gap. The principal design of such sensors was reported 15 years ago. Since then, sensors for almost 20 different GPCRs have been designed. If used with necessary controls and cautious interpretation, such sensors can contribute significantly to our understanding of the basic mechanisms of GPCR function and beyond. In this review, we will discuss the recent developments in this area of GPCR dynamics.

  • The Pharmacokinetics of Fumaric Acid Esters Reveal Their In Vivo Effects
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-11-25
    Ulrich Mrowietz, Peter John Morrison, Ina Suhrkamp, Margaret Kumanova, Bernd Clement

    Fumaric acid ester-based drugs are used for the treatment of psoriasis and multiple sclerosis. All licensed fumaric acid ester drugs contain dimethylfumarate (DMF) as the main active component. Due to the expanding use of oral DMF there is growing scientific interest in determining its as-yet-unknown mechanism of action. However, the pharmacology and chemistry of DMF are often not fully considered in the design and interpretation of experiments; namely, that while DMF is plasma-membrane permeable and has strong effects on many cell types in vitro, it is rapidly metabolized into membrane-impermeable monomethylfumarate (MMF) in vivo. This can lead to significant biological effects being erroneously assigned to DMF. Understanding the pharmacology of DMF means that future work can more closely reflect the state in vivo.

  • Single-Molecule Imaging of GPCR Interactions
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-11-17
    Davide Calebiro, Titiwat Sungkaworn

    G protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors and are of great interest as pharmacological targets. Although the occurrence of GPCR signaling nanodomains has long been hypothesized based on indirect evidence, this and other fundamental aspects of GPCR signaling have been difficult to prove. The advent of single-molecule microscopy methods, which allow direct visualization of individual membrane proteins with unprecedented spatiotemporal resolution, provides unique opportunities to address several of these open questions. Indeed, recent single-molecule studies have revealed that GPCRs and G proteins transiently interact with each other as well as with structural components of the plasma membrane, leading to the formation of dynamic complexes and ‘hot spots’ for GPCR signaling. Whereas we are only beginning to understand the implications of this unexpected level of complexity, single-molecule approaches are likely to play a crucial role to further dissect the protein–protein interactions that are at the heart of GPCR signaling.

  • Remodeling the Tumor Microenvironment with Emerging Nanotherapeutics
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-11-15
    Qin Chen, Guangxuan Liu, Shuo Liu, Hongyan Su, Yue Wang, Jingyu Li, Cong Luo

    The tumor microenvironment (TME) has profound impacts on cancer progression and remodeling of the TME has emerged as a strategy to facilitate cancer therapy. Recently, great progress in TME modulation has been made, especially with the rapid developments in nanomedicine. In this review we outline the latest advances in remodeling of the TME based on nanotherapeutics. First, novel strategies developed to modulate the tumor extracellular matrix (ECM) are discussed, including disruption, mimicking, and intervening in tumor ECM fabrication. Then, emerging tumor-associated fibroblast (TAF)-based nanotherapeutics are reviewed, including disruption and targeting of TAFs. Furthermore, recent developments in tumor vessel disruption and normalization are discussed. Finally, emerging approaches in response to tumor hypoxia are presented, with special emphasis on delivering oxygen, generating oxygen, and targeting tumor hypoxia.

  • Clodronate: A Vesicular ATP Release Blocker
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-11-13
    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. Its effectiveness is stronger, faster acting, and longer lasting than that of existing drugs such as pregabalin. Thus, clodronate might be a promising drug for attenuating chronic neuropathic pain and opens a new field of drug discovery as a presynaptic blocker for purinergic chemical transmission.

  • Insulin-Degrading Enzyme in the Fight against Alzheimer’s Disease
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-11-10
    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. Consequently, specific allosteric activation of IDE coupled with state-of-the-art compound delivery and CRISP-Cas9 technique of transgene insertion can be instrumental in the fight against AD and related neurodegenerative maladies.

  • NanoBRET Approaches to Study Ligand Binding to GPCRs and RTKs
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-11-10
    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 10 nm) 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. Here, we review the use of BRET from N-terminal NanoLuc-tagged GPCRs or a RTK to a receptor-bound fluorescent ligand to provide quantitative pharmacology of ligand–receptor interactions in living cells in real time.

  • Single-Molecule Analysis of G Protein-Coupled Receptor Stoichiometry: Approaches and Limitations
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-11-06
    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. Here, we discuss the types of SM imaging strategies used to examine GPCR stoichiometry and consider some of these caveats. We also emphasize that attempts to resolve the debate ought to rely on orthogonal approaches to measuring receptor stoichiometry.

  • Assays with Detection of Fluorescence Anisotropy: Challenges and Possibilities for Characterizing Ligand Binding to GPCRs
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-11-01
    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. FA assays have clear potential for implementation in drug screening systems, but also in studies of ligand-binding mechanisms for particular GPCRs.

  • Towards In Silico Prediction of the Immune-Checkpoint Blockade Response
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-10-28
    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. Several points for discussion are highlighted to inspire further research for improving ICB treatment. Continuing efforts are required to improve ICB response prediction and to identify novel predictive biomarkers by taking advantage of the rapid development of computational models and HTS techniques for effective and personalized cancer immunotherapy.

  • The Academic–Industrial Complexity: Failure to Launch
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-10-27
    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.

  • Temporal Bias: Time-Encoded Dynamic GPCR Signaling
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-10-23
    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. A dynamic feature such as temporal bias adds to the complexity of GPCR signaling bias and gives rise to the question whether this trait could be exploited to gain control over time-encoded cell physiology.

  • Challenges and Recent Advances in Medulloblastoma Therapy
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-10-20
    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. Combination therapies using multiple drugs and miRNAs could be effective approaches. In this review we discuss various MB subtypes, barriers, and novel therapeutic options which may be less toxic than current standard treatments.

  • Genetically Encoded FRET Biosensors to Illuminate Compartmentalised GPCR Signalling
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-10-17
    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. Here we review the use of these sensors in the GPCR field and how it has already provided invaluable advances towards our understanding of the complexity of GPCR signalling.

  • Leveraging Chemotype-Specific Resistance for Drug Target Identification and Chemical Biology
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-10-13
    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. We propose that chemotype-specific resistance, which is generally considered to be a limitation of molecularly targeted agents, can be leveraged to deconvolve the mechanism of action of drugs and to properly use chemical probes.

  • Spatial Intensity Distribution Analysis: Studies of G Protein-Coupled Receptor Oligomerisation
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-10-09
    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. We describe the application of SpIDA to investigate the oligomeric state of G protein-coupled receptors (GPCRs) at steady state and following cellular challenge, and consider how SpIDA may be used to explore GPCR quaternary organisation in pathophysiology and to stratify medicines.

  • Evidence-Based Precision Oncology with the Cancer Targetome
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-09-27
    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. The focus of this review is precision oncology but the discussion is highly relevant to targeted therapies in any area.

  • Psychedelic Drugs in Biomedicine
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-09-22
    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. Here, we summarize recent preclinical and clinical data in this field, discuss their pharmacological mechanisms of action, and outline critical areas for future studies of psychedelic drugs, with the goal of maximizing the potential benefits of translational psychedelic biomedicine to patients.

  • Designing Safer Analgesics via μ-Opioid Receptor Pathways
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-09-19
    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. In this review we outline recent progress towards the discovery of safer opioid analgesics.

  • The Action Radius of Oxytocin Release in the Mammalian CNS: From Single Vesicles to Behavior
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-09-09
    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. In the present review, based on anatomical, biochemical, electrophysiological, and behavioral studies, we propose a novel model of local OT actions in the central nervous system (CNS) via focused axonal release, which initiates intracellular signaling cascades in specific OT-sensitive neuronal populations and coordinated brain region-specific behaviors.

  • Activating or Inhibiting Nrf2?
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-09-05
    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.

  • Genetically Engineered Bacteria for Treating Human Disease
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-07-28
    Buyun Ma, Qiuwei Pan, Maikel P. Peppelenbosch

    Bacteria have now been harnessed to combat human diseases, especially to meet the challenge of antimicrobial resistance. Modulating the microbiome, particularly by genetically engineering the bacteria, has provided proof-of-concept as potential pharmacotherapy, but those involved in this field should engage in discussion as how to move forward.

  • An Overview of Novel Adjuvants Designed for Improving Vaccine Efficacy
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-06-28
    Srinivasa Reddy Bonam, Charalambos D. Partidos, Sampath Kumar M. Halmuthur, Sylviane Muller

    Adjuvants incorporated in prophylactic and/or therapeutic vaccine formulations impact vaccine efficacy by enhancing, modulating, and/or prolonging the immune response. In addition, they reduce antigen concentration and the number of immunizations required for protective efficacy, therefore contributing to making vaccines more cost effective. Our better understanding of the molecular mechanisms of immune recognition and protection has led research efforts to develop new adjuvants that are currently at various stages of development or clinical evaluation. In this review, we focus mainly on several of these promising adjuvants, and summarize recent work conducted in various laboratories to develop novel lipid-containing adjuvants

  • Targeting the Thioredoxin System for Cancer Therapy
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-06-22
    Junmin Zhang, Xinming Li, Xiao Han, Ruijuan Liu, Jianguo Fang

    Thioredoxin (Trx) and thioredoxin reductase (TrxR) are essential components of the Trx system which plays pivotal roles in regulating multiple cellular redox signaling pathways. In recent years TrxR/Trx have been increasingly recognized as an important modulator of tumor development, and hence targeting TrxR/Trx is a promising strategy for cancer treatment. In this review we first discuss the structural details of TrxR, the functions of the Trx system, and the rational of targeting TrxR/Trx for cancer treatment. We also highlight small-molecule TrxR/Trx inhibitors that have potential anticancer activity and review their mechanisms of action. Finally, we examine the challenges of developing TrxR/Trx inhibitors as anticancer agents and perspectives for selectively targeting TrxR/Trx.

  • FFA4/GPR120: Pharmacology and Therapeutic Opportunities
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-07-19
    Graeme Milligan, Elisa Alvarez-Curto, Brian D. Hudson, Rudi Prihandoko, Andrew B. Tobin

    Free Fatty Acid receptor 4 (FFA4), also known as GPR120, is a G-protein-coupled receptor (GPCR) responsive to long-chain fatty acids that is attracting considerable attention as a potential novel therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). Although no clinical studies have yet been initiated to assess efficacy in this indication, a significant number of primary publications and patents have highlighted the ability of agonists with potency at FFA4 to improve glucose disposition and enhance insulin sensitivity in animal models. However, the distribution pattern of the receptor suggests that targeting FFA4 may also be useful in other conditions, ranging from cancer to lung function. Here, we discuss and contextualise the basis for these ideas and the results to support these conclusions.

  • Interstrand Crosslink Repair as a Target for HDAC Inhibition
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-07-04
    Teodora Nikolova, Nicole Kiweler, Oliver H. Krämer

    DNA interstrand crosslinks (ICLs) covalently connect complementary DNA strands. Consequently, DNA replication and transcription are hampered, DNA damage responses (DDR) are initiated, and cell death is triggered. Therefore, drugs inducing ICLs are effective against rapidly growing cancer cells. However, tumors engage a complicated enzymatic machinery to repair and survive ICLs. Several factors, including the post-translational acetylation/deacetylation of lysine residues within proteins, control this network. Histone deacetylases (HDACs) modulate the expression and functions of DNA repair proteins which remove ICLs and control the accessibility of chromatin. Accordingly, histone deacetylase inhibitors (HDACi) are small, pharmacologically and clinically relevant molecules that sensitize cancer cells to ICL inducers. We discuss the mechanism of ICL repair and targets of HDACi within this pathway.

  • Applying Structure-Based Drug Design Approaches to Allosteric Modulators of GPCRs
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-06-22
    Miles Congreve, Christine Oswald, Fiona H. Marshall

    Structural insights have been revealed from X-ray co-complexes of a range of G protein-coupled receptors (GPCRs) and their allosteric ligands. The understanding of how small molecules can modulate the function of this important class of receptors by binding to a diverse range of pockets on and inside the proteins has had a profound impact on the structure-based drug design (SBDD) of new classes of therapeutic agents. The types of allosteric pockets and the mode of modulation as well as the advantages and disadvantages of targeting allosteric pockets (as opposed to the natural orthosteric site) are considered in the context of these new structural findings.

  • Early and Late CNS Inflammation in Alzheimer’s Disease: Two Extremes of a Continuum?
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-08-31
    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. Early disease-aggravating CNS inflammation might start decades before the presentation of severe cognitive impairments or dementia, and the nature of this process will co-evolve with the neuropathological progression from preclinical to clinical AD stages. This early CNS inflammation should be considered a promising therapeutic target as we continue searching for an unequivocal diagnosis of AD preclinical stages.

  • Immunomodulatory Properties of Plants and Mushrooms
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-08-30
    Jan Martel, Yun-Fei Ko, David M. Ojcius, Chia-Chen Lu, Chih-Jung Chang, Chuan-Sheng Lin, Hsin-Chih Lai, John D. Young

    Plants and mushrooms are used for medicinal purposes and the screening of molecules possessing biological activities. A single plant or mushroom may produce both stimulatory and inhibitory effects on immune cells, depending on experimental conditions, but the reason behind this dichotomy remains obscure. We present here a large body of experimental data showing that water extracts of plants and mushrooms usually activate immune cells, whereas ethanol extracts inhibit immune cells. The mode of extraction of plants and mushrooms may thus determine the effects produced on immune cells, possibly due to differential solubility and potency of stimulatory and inhibitory compounds. We also examine the possibility of using such plant and mushroom extracts to treat immune system disorders.

  • Targeting 12-Lipoxygenase As a Potential Novel Antiplatelet Therapy
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-08-29
    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. Recently, a selective 12-LOX inhibitor, ML355, was shown to decrease thrombosis without prolonging hemostasis. While published data suggests targeting 12-LOX is a viable approach, further work is required to determine the safety and effectiveness of 12-LOX inhibitors in humans.

  • Amyloid in Alzheimer’s Disease: Guilty Beyond Reasonable Doubt?
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-08-18
    Christian Behl

    Recently failed antiamyloidogenic trials call for an objective reassessment of the dominating amyloid cascade hypothesis of Alzheimer’s disease (AD). Ongoing efforts focusing on amyloid β protein (Aβ), its deposition, and its removal need to be complemented by more intensive research in new directions. Those may either integrate amyloid pathology or will propose pathogenetic routes independent of Aβ in the search for the causes of AD.

  • Li–Fraumeni Syndrome Disease Model: A Platform to Develop Precision Cancer Therapy Targeting Oncogenic p53
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-08-14
    Ruoji Zhou, An Xu, Julian Gingold, Louise C. Strong, Ruiying Zhao, Dung-Fang Lee

    Li–Fraumeni syndrome (LFS) is a rare hereditary autosomal dominant cancer disorder. Germline mutations in TP53, the gene encoding p53, are responsible for most cases of LFS. TP53 is also the most commonly mutated gene in human cancers. Because inhibition of mutant p53 is considered to be a promising therapeutic strategy to treat these diseases, LFS provides a perfect genetic model to study p53 mutation-associated malignancies as well as to screen potential compounds targeting oncogenic p53. In this review we briefly summarize the biology of LFS and current understanding of the oncogenic functions of mutant p53 in cancer development. We discuss the strengths and limitations of current LFS disease models, and touch on existing compounds targeting oncogenic p53 and in vitro clinical trials to develop new ones. Finally, we discuss how recently developed methodologies can be integrated into the LFS induced pluripotent stem cell (iPSC) platform to develop precision cancer therapy.

  • Targeting Mechanisms Linking COPD to Type 2 Diabetes Mellitus
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-08-07
    Mario Cazzola, Paola Rogliani, Luigino Calzetta, Davide Lauro, Clive Page, Maria Gabriella Matera

    Chronic obstructive pulmonary disease (COPD) and type 2 diabetes mellitus (T2DM) often coexist. The mechanistic links between these two diseases are complex, multifactorial, and not entirely understood, but they can influence the approach to treatment. Understanding whether COPD comes first followed by T2DM or vice versa, or whether the two diseases develop simultaneously due to common underlying mechanisms, is important for the development of novel therapeutic approaches to these two important diseases. In this review, we discuss the potential links between COPD and T2DM and pharmacological approaches that might target these links.

  • Therapeutic Potential of Ranibizumab in Corneal Neovascularization
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-06-09
    Marianne L. Shahsuvaryan

    Ranibizumab is a humanized, affinity-matured vascular endothelial growth factor (VEGF) antibody fragment that neutralizes all isoforms of VEGF and is FDA approved for use in ophthalmology. Recently it was suggested that ranibizumab may be useful in the treatment of corneal neovascularization, but in reality this therapy is not yet evidence based.

  • Reprogramming of the Tumor in the Hypoxic Niche: The Emerging Concept and Associated Therapeutic Strategies
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-06-12
    Guan-Zhong Qiu, Ming-Zhu Jin, Jin-Xiang Dai, Wei Sun, Ji-Hong Feng, Wei-Lin Jin

    Hypoxia exerts a profound impact on diverse aspects of cancer biology. Increasing evidence has revealed novel functions of hypoxia in cancer cell epigenomics, epitranscriptomics, metabolism, and intercellular communication, all hotspots of cancer research. Several drugs have been developed to target intratumoral hypoxia and have entered clinical trials to treat refractory tumors. However, direct targeting of hypoxia signaling still has limitations in the clinic with regard to cancer progression and resistance to therapy. Comprehensive understanding of the molecular mechanisms by which hypoxia reshapes tumors and their microenvironment, as well as how tumor cells adapt to and thrive in hypoxic conditions, will therefore continue to be a focus of cancer research and will provide new directions for hypoxic tumor treatment.

  • Aurora A Kinase Is a Priority Pharmaceutical Target for the Treatment of Cancers
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-06-07
    Arun Prasath Damodaran, Lucie Vaufrey, Olivia Gavard, Claude Prigent

    Aurora kinases control multiple events during cell cycle progression and are essential for mitotic and meiotic bipolar spindle assembly and function. There are three Aurora kinases in mammals, some of which have oncogenic properties and all of which are overexpressed in multiple cancers. Pharmaceutical companies quickly made these kinases priority targets for the development of inhibitors to be used as cancer treatments. In this review, we focus on Aurora A, against which several inhibiting compounds have been discovered and made available; however, even though some of these compounds underwent clinical trials, none have yet gone beyond Phase III trials. The varying efficiencies and particularities of these drugs raise several questions that are explored in this review: is Aurora A even a good target? What biomarkers can we use to measure its activity in vivo? How can we improve the Aurora A-inhibiting drugs?

  • Targeting PAR1: Now What?
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-05-27
    Robert Flaumenhaft, Karen De Ceunynck

    Protease-activated receptors (PARs) are a ubiquitously expressed class of G-protein-coupled receptors (GPCRs) that enable cells to respond to proteases in the extracellular environment in a nuanced and dynamic manner. PAR1 is the archetypal family member and has been the object of large-scale drug development programs since the 1990s. Vorapaxar and drotrecogin-alfa are approved PAR1-targeted therapeutics, but safety concerns have limited the clinical use of vorapaxar and questions regarding the efficacy of drotrecogin-alfa led to its withdrawal from the market. New understanding of mechanisms of PAR1 function, discovery of improved strategies for modifying PAR1 function, and identification of novel indications for PAR1 modulators have provided new opportunities for therapies targeting PAR1. In this review, we critically evaluate prospects for the next generation of PAR1-targeted therapeutics.

  • Binding Kinetics and Pathways of Ligands to GPCRs
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-06-20
    Andrea Strasser, Hans-Joachim Wittmann, Roland Seifert

    Previously, drugs were developed focusing on target affinity and selectivity. However, it is becoming evident that the drug–target residence time, related to the off-rate, is an important parameter for successful drug development. The residence time influences both the on-rate and overall effectiveness of drugs. Furthermore, ligand binding is now appreciated to be a multistep process because metastable and/or intermediate binding sites in the extracellular region have been identified. In this review, we summarize experimental ligand-binding data for G-protein-coupled receptors (GPCRs), and their binding pathways, analyzed by molecular dynamics (MD). The kinetics of drug binding to GPCRs are complex and depend on several factors, including charge distribution on the receptor surface, ligand–receptor interactions in the binding channel and the binding site, or solvation.

  • The Cardiovascular Pharmacology of Nonsteroidal Anti-Inflammatory Drugs
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-06-23
    Tilo Grosser, Emanuela Ricciotti, Garret A. FitzGerald

    The principal molecular mechanisms underlying the cardiovascular (CV) and renal adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs), such as myocardial infarction and hypertension, are understood in more detail than most side effects of drugs. Less is known, however, about differences in the CV safety profile between chemically distinct NSAIDs and their relative predisposition to complications. In review article, we discuss how heterogeneity in the pharmacokinetics and pharmacodynamics of distinct NSAIDs may be expected to affect their CV risk profile. We consider evidence afforded by studies in model systems, mechanistic clinical trials, a meta-analysis of randomized controlled trials, and two recent large clinical trials, Standard Care vs. Celecoxib Outcome Trial (SCOT) and Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION), designed specifically to compare the CV safety of the cyclooxygenase-2-selective NSAID, celecoxib, with traditional NSAIDs. We conclude that SCOT and PRECISION have apparently not compared equipotent doses and have other limitations that bias them toward underestimation of the relative risk of celecoxib.

  • Folding Underlies Bidirectional Role of GPR37/Pael-R in Parkinson Disease
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-06-16
    Lina Leinartaité, Per Svenningsson

    Since conformational flexibility, which is required for the function of a protein, comes at the expense of structural stability, many proteins, including G-protein-coupled receptors (GPCRs), are under constant risk of misfolding and aggregation. In this regard GPR37 (also named PAEL-R and ETBR-LP-1) takes a prominent role, particularly in relation to Parkinson disease (PD). GPR37 is a substrate for parkin and accumulates abnormally in autosomal recessive juvenile parkinsonism, contributing to endoplasmic reticulum stress and death of dopaminergic neurons. GPR37 also constitutes a core structure of Lewy bodies, demonstrating a more general involvement in PD pathology. However, if folded and matured properly, GPR37 seems to be neuroprotective. Moreover, GPR37 modulates functionality of the dopamine transporter and the dopamine D2 receptor and stimulates dopamine neurotransmission. Here we review the multiple roles of GPR37 with relevance to potential disease modification and symptomatic therapies of PD and highlight unsolved issues in this field.

  • Structural Principles of Fluorescent RNA Aptamers
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-07-17
    Robert J. Trachman, Lynda Truong, Adrian R. Ferré-D'Amaré

    Several aptamer RNAs have been selected in vitro that bind to otherwise weakly fluorescent small molecules and enhance their fluorescence several thousand-fold. By genetically tagging cellular RNAs of interest with these aptamers and soaking cells in their cell-permeable cognate small-molecule fluorophores, it is possible to use them to study RNA localization and trafficking. These aptamers have also been fused to metabolite-binding RNAs to generate fluorescent biosensors. The 3D structures of three unrelated fluorogenic RNAs have been determined, and reveal a shared reliance on base quadruples (tetrads) to constrain the photo-excited chromophore. The structural diversity of fluorogenic RNAs and the chemical diversity of potential fluorophores to be activated are likely to yield a variety of future fluorogenic RNA tags that are optimized for different applications in RNA imaging and in the design of fluorescent RNA biosensors.

  • Towards a Structural View of Drug Binding to hERG K+ Channels
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-07-12
    Jamie I. Vandenberg, Eduardo Perozo, Toby W. Allen

    The human ether-a-go-go-related gene (hERG) K+ channel is of great medical and pharmaceutical relevance. Inherited mutations in hERG result in congenital long-QT syndrome which is associated with a markedly increased risk of cardiac arrhythmia and sudden death. hERG K+ channels are also remarkably susceptible to block by a wide range of drugs, which in turn can cause drug-induced long-QT syndrome and an increased risk of sudden death. The recent determination of the near-atomic resolution structure of the hERG K+ channel, using single-particle cryo-electron microscopy (cryo-EM), provides tremendous insights into how these channels work. It also suggests a way forward in our quest to understand why these channels are so promiscuous with respect to drug binding.

  • Lessons Learned from Two Decades of Anticancer Drugs
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-07-11
    Zhichao Liu, Brian Delavan, Ruth Roberts, Weida Tong

    Tremendous efforts have been made to elucidate the basis of cancer biology with the aim of promoting anticancer drug development. Especially over the past 20 years, anticancer drug development has developed from conventional cytotoxic agents to target-based and immune-related therapies. Consequently, more than 200 anticancer drugs are available on the market. However, anticancer drug development still suffers high attrition during the later phases of clinical development and is considered to be a difficult and risky therapeutic category within the drug development arena. The disappointing performance of investigational anticancer candidates implies that there are some shortcomings in the translation of preclinical in vitro and in vivo models to humans, and that heterogeneity in the patient population presents a significant challenge. Here, we summarize both successful and failed experiences in anticancer development during the past 20 years and help identify why the current paradigm may be suboptimal. We also offer potential strategies for improvement.

  • Sphingosine Kinase 2 in Autoimmune/Inflammatory Disease and the Development of Sphingosine Kinase 2 Inhibitors
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-06-09
    Nigel J. Pyne, David R. Adams, Susan Pyne

    The purpose of this Opinion is to present a case for targeting sphingosine kinase 2 (SK2) in autoimmune/inflammatory disease. Data obtained using Sphk2−/− mice suggest that SK2 is an anti-inflammatory enzyme, although this might be misleading because of a compensatory increase in the expression of a second isoform, sphingosine kinase 1 (SK1), which functions as a proinflammatory enzyme. SK2 is involved in regulating interleukin (IL)-12/interferon gamma (IFN-γ) and histone deacetylase-1/2 (HDAC-1/2) signalling and, potentially, retinoid-related orphan receptor gamma t (ROR-γt) stability linked with T helper (Th) 17 cell polarisation. Therefore, there is a need to develop highly potent SK2 inhibitors with selectivity over SK1 to clearly define the role of SK2 in autoimmune/inflammatory disease. Structural determinants of SK2 relative to SK1 will enable the design of selective SK2 inhibitors.

  • Targeting Free Radicals in Oxidative Stress-Related Human Diseases
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-05-24
    Patrik Poprac, Klaudia Jomova, Miriama Simunkova, Vojtech Kollar, Christopher J. Rhodes, Marian Valko

    Cancer and Alzheimer’s disease (AD) are characterized by (i) opposing biological mechanisms, (ii) an inverse correlation between their incidences, and (iii) oxidative stress being a common denominator of both diseases. Increased formation of reactive oxygen species (ROS) in cancer cells from oncogenic signaling and/or metabolic disturbances leads to upregulation of cellular antioxidant capacity to maintain ROS levels below a toxic threshold. Combining drugs that induce high levels of ROS with compounds that suppress cellular antioxidant capacity by depleting antioxidant systems [glutathione (GSH), superoxide dismutase (SOD), and thioredoxin (TRX)] and/or targeting glucose metabolism represents a potential anticancer strategy. In AD, free metals and/or Aβ:metal complexes may cause damage to biomolecules in the brain (via Fenton reaction), including DNA. Metal chelation, based on the application of selective metal chelators or metal delivery, may induce neuroprotective signaling and represents a promising therapeutic strategy. This review examines therapeutic strategies based on the modulation of oxidative stress in cancer and AD.

  • Contribution of Clinical Neuroimaging to the Understanding of the Pharmacology of Methylphenidate
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-04-24
    Luc Zimmer

    Methylphenidate (MPH) is currently the most widely used molecule in the pharmacologic treatment of attention-deficit hyperactivity disorder (ADHD). Although experience of its application now extends over several decades, its psychotropic nature, prolonged use in children, and chemical relation to amphetamines still raise doubts in the minds of prescribers and the families of the patients. Brain imaging has shed considerable light on the neuropharmacology of MPH. The two main in vivo neuroimaging techniques are positron-emission tomography (PET) and magnetic resonance imaging (MRI), and these can be applied in both animal models and humans. The present review seeks to show how human molecular and functional imaging has contributed to determining not only the molecular targets of MPH, and the action kinetics of the various pharmaceutical forms available, but also the connectivity and brain networks activated by treatment. We also discuss the perspectives opened up by new hybrid PET–MRI techniques that enable multimodal tracking of the impact of methylphenidate on neurotransmission.

  • Emerging Paradigms of G Protein-Coupled Receptor Dephosphorylation
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-05-04
    Andrea Kliewer, Rainer K. Reinscheid, Stefan Schulz

    Elucidation of the molecular mechanisms underlying G protein-coupled receptor (GPCR) dephosphorylation remains a major challenge. While specific GPCR phosphatases (GRPs) have eluded identification, prevailing models propose that receptors must first internalize into acidic endosomes to become dephosphorylated in a housekeeping-like process. Recently, phosphosite-specific antibodies, combined with siRNAs targeting specific phosphatase transcripts, have facilitated the identification of distinct protein phosphatase 1 (PP1) and PP2 catalytic subunits as bona fide GRPs. Similar to phosphorylation, GPCR dephosphorylation is temporally and spatially regulated, starting immediately after receptor activation at the plasma membrane and continuing along the endocytic pathway. Dephosphorylation disrupts receptor–arrestin complexes, thus terminating arrestin-dependent signaling. Partially dephosphorylated GPCRs may remain membrane bound for renewed agonist activation while others undergo endocytosis. After internalization, further dephosphorylation facilitates the transition into the recycling pathway, leading to either plasma membrane repopulation or lysosomal degradation. These findings reveal unappreciated cellular sites and regulatory functions of receptor dephosphorylation and call for revised models of the GPCR activation/deactivation cycle.

  • A Brief Overview of Tauopathy: Causes, Consequences, and Therapeutic Strategies
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-04-25
    Miranda E. Orr, A. Campbell Sullivan, Bess Frost

    There are currently no disease-modifying therapies for the treatment of tauopathies, a group of progressive neurodegenerative disorders that are pathologically defined by the presence of tau protein aggregates in the brain. Current challenges for the treatment of tauopathies include the inability to diagnose early and to confidently discriminate between distinct tauopathies in patients, alongside an incomplete understanding of the cellular mechanisms involved in pathogenic tau-induced neuronal death and dysfunction. In this review, we describe current diagnostic and therapeutic strategies, known drivers of pathogenic tau formation, recent contributions to our current mechanistic understanding of how pathogenic tau induces neuronal death, and potential diagnostic and therapeutic approaches.

  • Roles of Diacylglycerols and Ceramides in Hepatic Insulin Resistance
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-05-24
    Max C. Petersen, Gerald I. Shulman

    Although ample evidence links hepatic lipid accumulation with hepatic insulin resistance, the mechanistic basis of this association is incompletely understood and controversial. Diacylglycerols (DAGs) and ceramides have emerged as the two best-studied putative mediators of lipid-induced hepatic insulin resistance. Both lipids were first associated with insulin resistance in skeletal muscle and were subsequently hypothesized to mediate insulin resistance in the liver. However, the putative roles for DAGs and ceramides in hepatic insulin resistance have proved more complex than originally imagined, with various genetic and pharmacologic manipulations yielding a vast and occasionally contradictory trove of data to sort. In this review we examine the state of this field, turning a critical eye toward both DAGs and ceramides as putative mediators of lipid-induced hepatic insulin resistance.

  • The Future of Cysteine Cathepsins in Disease Management
    Trends Pharmacol. Sci. (IF 12.797) Pub Date : 2017-06-28
    Lovro Kramer, Dušan Turk, Boris Turk

    Since the discovery of the key role of cathepsin K in bone resorption, cysteine cathepsins have been investigated by pharmaceutical companies as drug targets. The first clinical results from targeting cathepsins by activity-based probes and substrates are paving the way for the next generation of molecular diagnostic imaging, whereas the majority of antibody–drug conjugates currently in clinical trials depend on activation by cathepsins. Finally, cathepsins have emerged as suitable vehicles for targeted drug delivery. It is therefore timely to review the future of cathepsins in drug discovery. We focus here on inflammation-associated diseases because dysregulation of the immune system accompanied by elevated cathepsin activity is a common feature of these conditions.

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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