Pharmacology

  • Article
    | Open Access

    Vilazodone (VLZ) is a drug for the treatment of major depressive disorders that targets the serotonin transporter (SERT). Here, the authors combine pharmacology measurements and cryo-EM structural analysis to characterize VLZ binding to SERT and observe that VLZ exhibits non-competitive inhibition of serotonin transport and binds with nanomolar affinity to an allosteric site in SERT.

    • Per Plenge
    • , Dongxue Yang
    •  & Claus J. Loland
  • Article
    | Open Access

    Various GPCRs display constitutive ligand-independent activity, but it remains unclear whether ligand-dependent and -independent conformations differ. Here the authors demonstrate the recognition and blocking of G protein recruitment of either the ligand-bound active, or the constitutively active apo-conformation of the viral GPCR US28 by different nanobodies that target similar intracellular loops of the receptor.

    • Timo W. M. De Groof
    • , Nick D. Bergkamp
    •  & Martine J. Smit
  • Article
    | Open Access

    There is a need to optimise cryo-EM data acquisition approaches to improve the resolution of GPCR cryo-EM structures to better than 2.5 Å, in order to use them for structure-based drug design purposes. Here, the authors present a systematic analysis of the main cryo-EM experimental parameters using three GPCRs as test cases, which is also of interest for the cryo-EM structure determination of other small membrane proteins.

    • Radostin Danev
    • , Matthew Belousoff
    •  & Patrick M. Sexton
  • Article
    | Open Access

    Mutations in ryanodine receptor 1 (RyR1), a Ca2+ release channel in skeletal muscle, cause malignant hyperthermia (MH) and are involved in heat stroke. Here, the authors show that an oxolinic acid-derivative RyR1 inhibitor effectively prevents and treats MH and heat stroke in various MH mouse models.

    • Toshiko Yamazawa
    • , Takuya Kobayashi
    •  & Takashi Murayama
  • Article
    | Open Access

    Nucleoside analogs (NNA), such as acyclovir (ACV) and ganciclovir (GCV), are widely used as anti-virals to treat herpes virus infection. Here, Nishii et al. show that diphosphatase NUDT15 hydrolyzes ACV and GCV, therewith reducing NNA activity in vitro and link NUDT15 variation to inter-patient variability in ACV and GCV therapeutic effects.

    • Rina Nishii
    • , Takanori Mizuno
    •  & Jun J. Yang
  • Article
    | Open Access

    Mitragynine (MG) is an indole alkaloid from kratom plant that binds opioid receptors and as such presents a scaffold for the development of atypical opioid receptor modulators. Here, the authors report a synthetic method for selective functionalization of the C11 position of MG, and show that this position is essential for fine-tuning opioid receptor signaling efficacy.

    • Srijita Bhowmik
    • , Juraj Galeta
    •  & Dalibor Sames
  • Article
    | Open Access

    The glucagon-like peptide-1 (GLP-1) receptor is a key regulator of glucose homeostasis and a drug target for type 2 diabetes but available GLP-1R agonists are suboptimal due to several side-effects. Here authors report the cryo-EM structure of GLP-1R bound to an ago-allosteric modulator in complex with heterotrimeric Gs which offers insights into the molecular details of ago-allosterism.

    • Zhaotong Cong
    • , Li-Nan Chen
    •  & Ming-Wei Wang
  • Article
    | Open Access

    Recently, a class of non-catechol Dopamine D1 receptor (D1R) selective agonists with novel scaffold and improved pharmacological properties were reported. Here, authors report the crystal structure of D1R in complex with stimulatory G protein (Gs) and a non-catechol agonist Compound 1 which explains the selectivity of this scaffold for D1R over other aminergic receptors and the mechanism of activating D1R.

    • Bingfa Sun
    • , Dan Feng
    •  & Brian K. Kobilka
  • Article
    | Open Access

    Metals such as calcium and potassium have long been known to regulate the diameter of arteries that control blood flow. Here, we report that zinc causes relaxation of blood vessels and reduces blood pressure by its coordinated action in sensory nerves, endothelium and smooth muscle cells.

    • Ashenafi H. Betrie
    • , James A. Brock
    •  & Scott Ayton
  • Article
    | Open Access

    The circadian clock is an internal mechanism that controls various physiological processes, such as the sleep-wake cycle, but its precise regulation is challenging. Here, the authors develop a visible light-responsive inhibitor of casein kinase I which controls the period and phase of cellular and tissue circadian rhythms in a reversible manner.

    • Dušan Kolarski
    • , Carla Miró-Vinyals
    •  & Ben L. Feringa
  • Article
    | Open Access

    The mechanism by which parathyroid hormone mediates the switch from bone resorption to bone formation is unclear. Here, the authors show that SLPI regulates the communication between osteoblasts and osteoclasts to promote the anabolic effect of parathyroid hormone.

    • Akito Morimoto
    • , Junichi Kikuta
    •  & Masaru Ishii
  • Article
    | Open Access

    Clinical trials of novel therapeutics for Alzheimer’s Disease (AD) have provided largely negative results, so far. Here, the authors present a machine learning framework that quantifies potential associations between the pathology of AD severity and gene-based molecular mechanisms to enable drug repurposing.

    • Steve Rodriguez
    • , Clemens Hug
    •  & Artem Sokolov
  • Article
    | Open Access

    The human neuropeptide Y receptor Y2 (Y2R) is a drug target for the treatment of obesity and anxiety. Crystal structure of Y2R bound to a selective antagonist and accompanying mutagenesis provide insights into ligand recognition and subtype specificity of NPY receptors.

    • Tingting Tang
    • , Christin Hartig
    •  & Beili Wu
  • Article
    | Open Access

    Nonalcoholic steatohepatitis (NASH) and associated liver fibrosis have limited therapy options. Here the authors report a novel adiponectin-based dual agonist for adiponectin receptors 1 and 2 with a longer half-life, and show that it ameliorates NASH and liver fibrosis in mouse models.

    • Hongjiao Xu
    • , Qian Zhao
    •  & Xianxing Jiang
  • Article
    | Open Access

    Propionic acidemia is a serious pediatric inherited disorder with no effective treatments. Here the authors demonstrate that delivering dual mRNAs as an enzyme replacement approach can be used as an effective therapy in a mouse model of propionic acidemia, with potential applicability to chronically administer multiple mRNAs in other genetic disorders.

    • Lei Jiang
    • , Ji-Sun Park
    •  & Lin T. Guey
  • Article
    | Open Access

    Both agonism and antagonism of the glucose-dependent insulinotropic polypeptide receptor (GIPR) lead to weight loss in combination with glucagon-like peptide-1 receptor agonists in preclinical models. Here the authors show that this may be explained by desensitization of GIPR activity by chronic GIPR agonism in vitro and in vivo.

    • Elizabeth A. Killion
    • , Michelle Chen
    •  & David J. Lloyd
  • Article
    | Open Access

    The αvβ6 integrin is key in activating the pro-fibrotic cytokine TGFβ in idiopathic pulmonary fibrosis. Here, the authors show an inhaled small molecule αvβ6 inhibitor GSK3008348 induces prolonged inhibition of TGFβ signaling pathways in human and murine models of lung fibrosis via αvβ6 degradation.

    • Alison E. John
    • , Rebecca H. Graves
    •  & Robert J. Slack
  • Article
    | Open Access

    Cyclin-dependent kinase (CDK) inhibitors are widely used both in the clinic and for basic research aimed at dissecting the specific cellular functions of specific CDKs. Here, the authors report the development of a panel of fluorescent reporter probes and provide a comprehensive profile of the inhibitory activity of several CDK inhibitors towards all 21 CDKs in living cells.

    • Carrow I. Wells
    • , James D. Vasta
    •  & Matthew B. Robers
  • Article
    | Open Access

    The gut microbiota can alter the effects of anticancer fluoropyrimidines such as 5-fluorodeoxyuridine (FUdR) in the model organism C. elegans. Here, the authors show that these effects are further affected by diet, and dietary thymidine and serine increase FUdR toxicity in C. elegans via different mechanisms.

    • Wenfan Ke
    • , James A. Saba
    •  & Eyleen J. O’Rourke
  • Article
    | Open Access

    Antibodies conjugated to bioactive compounds can allow targeted delivery of therapeutics. Here the authors present a strategy for fusing nanobodies to suboptimal GPCR peptide ligands to potently and selectively activate receptors.

    • Ross W. Cheloha
    • , Fabian A. Fischer
    •  & Hidde L. Ploegh
  • Article
    | Open Access

    Drugs targeting dysregulated ERK1/2 signaling can cause severe cardiac side effects, precluding their wide therapeutic application. Here, a new and cardio-safe targeting strategy is presented that interferes with ERK dimerization to prevent pathological ERK1/2 signaling in the heart and cancer.

    • Angela Tomasovic
    • , Theresa Brand
    •  & Kristina Lorenz
  • Article
    | Open Access

    Quantitative profiling of small molecule-protein binding in cells can aid basic biochemical research and drug discovery. Here, the authors develop the Heat Shock Protein Inhibition Protein Stability Assay (HIPStA) as a high-throughput method to assess cellular target engagement and identify new drug targets.

    • Kelvin F. Cho
    • , Taylur P. Ma
    •  & Robert A. Blake
  • Article
    | Open Access

    WNT-Frizzled (FZD) signaling plays a critical role in embryonic development, tissue homeostasis and human disease but no small molecule drugs targeting FZD with distinct efficacy have emerged so far. Here, authors identify the Smoothened agonist SAG1.3 as a partial agonist for FZD6 with limited subtype selectivity.

    • Paweł Kozielewicz
    • , Ainoleena Turku
    •  & Gunnar Schulte
  • Article
    | Open Access

    Counterfeit medicines are a threat to patient health and public safety. Here, the authors use random patterns formed by fluorescent silk microparticles with various excitation and emission pairs as an edible physical unclonable function that can directly be attached onto the surface of medicines.

    • Jung Woo Leem
    • , Min Seok Kim
    •  & Young L. Kim
  • Article
    | Open Access

    FXR agonists have been investigated for the treatment of non-alcoholic steatohepatitis and liver fibrosis but the clinical efficacy is not optimal. Here the authors show that enhanced FXR SUMOylation in activated hepatic stellate cells reduces FXR signaling and that this can be rescued by SUMOylation inhibitors.

    • Jiyu Zhou
    • , Shuang Cui
    •  & Haiping Hao
  • Article
    | Open Access

    DNA-dependent protein kinase (DNA-PK) plays a major role in the DNA damage response upon double-strand break formation. Here, the authors show that the DNA-PK inhibitor AZD7648, enhances the activity of radiotherapy, chemotherapy and the PARP inhibitor olaparib in multiple mouse tumour models.

    • Jacqueline H. L. Fok
    • , Antonio Ramos-Montoya
    •  & Elaine B. Cadogan
  • Article
    | Open Access

    Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a powerful tool for neuroscience, but the standard DREADD ligand, CNO, has significant drawbacks. Here the authors report two novel high-potency DREADD ligands and a novel DREADD radiotracer for imaging purposes.

    • Jordi Bonaventura
    • , Mark A. G. Eldridge
    •  & Michael Michaelides
  • Article
    | Open Access

    Besides mechanical forces, the mechanosensitive channel Piezo1 is activated by the small molecule Yoda1 through an unknown mechanism. Here, using molecular dynamics simulations, calcium imaging and electrophysiology, the authors identify an allosteric Yoda1 binding pocket located in the putative mechanosensory domain.

    • Wesley M. Botello-Smith
    • , Wenjuan Jiang
    •  & Yun Luo
  • Article
    | Open Access

    Identifying ligands which activate the specific effectors driving particular in vivo drug effects remains challenging. Here, the authors apply unsupervised clustering of pharmacodynamic parameters to classify GPCR ligands into different categories with similar signaling profiles and shared frequency of report of side effects.

    • Besma Benredjem
    • , Jonathan Gallion
    •  & Graciela Pineyro
  • Article
    | Open Access

    Allosteric GPCR modulators can achieve exquisite subtype selectivity, but the underlying mechanism is unclear. Using molecular dynamics simulations, the authors here identify a previously undetected dynamic pocket in muscarinic GPCRs that is critical for subtype selectivity of allosteric modulators.

    • Scott A. Hollingsworth
    • , Brendan Kelly
    •  & Ron O. Dror
  • Article
    | Open Access

    Primaquine (PQ) is a widely used anti-malaria drug, but its mechanism of action is unclear. Here, Camarda et al. show that PQ’s activity against liver and sexual Plasmodium stages depends on generation of hydroxylated-PQ metabolites (OH-PQm), which, undergoing further reactions, results in production of H2O2.

    • Grazia Camarda
    • , Piyaporn Jirawatcharadech
    •  & Giancarlo A. Biagini
  • Article
    | Open Access

    The use of nonsteroidal anti-inflammatory drugs inhibiting COX-1/2 is associated with an increased risk of heart failure. Here the authors show that mPGES-1, a therapeutic target downstream of COX enzymes, protects from cardiac ischemia/reperfusion injury, limiting leukocyte-endothelial interactions and preserving microvascular perfusion partly via the endothelial EP4 receptor.

    • Liyuan Zhu
    • , Chuansheng Xu
    •  & Miao Wang
  • Article
    | Open Access

    A key challenge is to find/re-purpose approved drugs that could be used in humans to induce autophagy-associated clearance of neurodegenerative proteins. Here, authors demonstrate that felodipine, an anti-hypertensive drug, can induce autophagy and clear a variety of aggregated neurodegenerative disease-associated proteins in mouse brains at plasma concentrations similar to those that would be seen in humans taking the drug.

    • Farah H. Siddiqi
    • , Fiona M. Menzies
    •  & David C. Rubinsztein
  • Article
    | Open Access

    Non-adherence to daily drug regimens is responsible for many negative clinical effects including drug resistance in life-long treatments for HIV. Here, the authors report on a HIV prodrug nanoparticle platform for long-acting sustained release of water-soluble drug compounds following injection.

    • James J. Hobson
    • , Amer Al-khouja
    •  & Steve P. Rannard
  • Article
    | Open Access

    Class F receptors are therapeutic targets in human disease and understanding their structural changes during receptor activation may provide important pharmacological insight. Here, the authors combine computational and experimental methods to identify a molecular switch in TM6/7 of Class F receptors that mediates receptor activation.

    • Shane C. Wright
    • , Paweł Kozielewicz
    •  & Gunnar Schulte
  • Article
    | Open Access

    Tolerance and other side effects are important limitations to the use of opioids as analgesics. In this study, the authors generated mice lacking phosphorylation sites on the µ-opioid receptor to assess their contribution to the analgesic, tolerance and side effect profile of opioid analgesics.

    • A. Kliewer
    • , F. Schmiedel
    •  & S. Schulz
  • Article
    | Open Access

    The precise relationship between neurobehavioural effects and neurotransmitter effects of psychiatric drugs are not always understood. Here the authors develop a database documenting the neurotransmitter response in rats to 258 different neuropsychiatric drugs, and conclude that this neurotransmitter response does not, in general, reflect the current categorisation of those drugs.

    • Hamid R. Noori
    • , Lewis H. Mervin
    •  & Rainer Spanagel
  • Article
    | Open Access

    Vitamin E metabolites are proposed to have signalling capacity, but how they may regulate immune responses is still unclear. Here the authors show that a vitamin E metabolite, α-T-13′-COOH, can inhibit 5-lipoxygenase and thereby suppress the synthesis of lipid mediators of immune activation and inflammatory responses.

    • Helmut Pein
    • , Alexia Ville
    •  & Andreas Koeberle
  • Article
    | Open Access

    While drugs can interact in both target and off-target cell types, more favorable interaction in the target cell may nevertheless allow for a therapeutic window. Here, the authors show, using two yeast species as a model, that differential drug interactions indeed adjust the selective window.

    • Zohar B. Weinstein
    • , Nurdan Kuru
    •  & Murat Cokol
  • Article
    | Open Access

    Little is known about the contribution of germline genetic variants to cancer drug sensitivity. Here, the authors devise an approach for joint analysis of germline variants and somatic mutations, identifying substantial germline contributions to variation in drug sensitivity.

    • Michael P. Menden
    • , Francesco Paolo Casale
    •  & Oliver Stegle
  • Article
    | Open Access

    Ceramides are signalling molecules that regulate several physiological functions including insulin sensitivity. Here the authors report a selective ceramide synthase 1 inhibitor that counteracts lipid accumulation within the muscle and adiposity by increasing fatty acid oxidation but without affecting insulin sensitivity in mice fed with an obesogenic diet.

    • Nigel Turner
    • , Xin Ying Lim
    •  & Anthony S. Don
  • Article
    | Open Access

    Chronic itch affects about 10% of the general population, however current treatments are largely ineffective. Here, the authors show that targeting of inhibitory α2 and α3GABAA receptors reduces itch in mice and in a canine model, suggesting this a potentially useful therapeutic approach.

    • William T. Ralvenius
    • , Elena Neumann
    •  & Hanns Ulrich Zeilhofer
  • Article
    | Open Access

    The capsaicin receptor TRPV1 has been structurally characterized, but the capsaicin activation dynamics remain elusive. Here authors use fluorescent unnatural amino acid incorporation, computational modeling and Φ-analysis to derive the capsaicin-bound open state model and reveal the capsaicin induced conformational changes.

    • Fan Yang
    • , Xian Xiao
    •  & Jie Zheng
  • Article
    | Open Access

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor. Here the authors provide insights into PPARγ activation by combining fluorine (19F) NMR and molecular dynamics simulations to characterize the nuclear receptor conformational ensemble in solution and the response of this ensemble to ligand and coregulatory peptide binding.

    • Ian M. Chrisman
    • , Michelle D. Nemetchek
    •  & Travis S. Hughes