Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Structural determinants of TRPV4 inhibition and identification of new antagonists with antiviral activity.
Doñate-Macian P
,
Duarte Y
,
Rubio-Moscardo F
,
Pérez-Vilaró G
,
Canan J
,
Díez J
,
González-Nilo F
,
Valverde MA
.
???displayArticle.abstract???
BACKGROUND AND PURPOSE: The transient receptor potential vanilloid 4 (TRPV4) cation channel participates in multiple physiological processes and is also at the core of different diseases, making this channel an interesting pharmacological target with therapeutic potential. However, little is known about the structural elements governing its inhibition.
EXPERIMENTAL APPROACH: We have now combined in silico drug discovery and molecular dynamics simulation based on Xenopus tropicalis xTRPV4 structure with functional studies measuring cell Ca2+ influx mediated by human TRPV4 channel to characterize the binding site of known TRPV4 inhibitors and to identify novel small molecule channel modulators.
KEY RESULTS: We have found that the inhibitor HC067047 binds to a pocket conformed by residues from S2-S3 linker (xTRPV4-D542), S4 (xTRPV4-M583 and Y587 and S5 (xTRPV4-D609 and F613). This pocket was also used for structure-based virtual screening in the search of novel channel modulators. Forty potential hits were selected based on the lower docking scores (from ~250,000 compounds) and their effect upon TRPV4 functionally tested. Three were further analysed for stability using molecular dynamics simulation and functionally tested on TRPV4 channels carrying mutations in the binding pocket. Compound NSC151066, shown to require residue xTRPV4-M583 for its inhibitory effect, presented an IC50 of 145 nM and demonstrated to be an effective antiviral against Zika virus with a potency similar to HC067047.
CONCLUSION AND IMPLICATIONS: Together, we propose structural insights into the inhibition of TRPV4 and how this information can be used for the design of novel channel modulators.
LINKED ARTICLES: This article is part of a themed issue on Structure Guided Pharmacology of Membrane Proteins (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.14/issuetoc.
1170733 Chilean Fondo Nacional de Desarrollo Tecnológico (FONDECYT), BFU2016-80039-R Spanish Ministerio de Ciencia, Innovación y Universidades, RTI2018-099718 Spanish Ministerio de Ciencia, Innovación y Universidades, P029-022-F The Centro Interdisciplinario de Neurociencia de Valparaíso is a Millennium Institute supported by the Millennium Scientific Initiative of the Ministerio de Economía, Fomento y Turismo, W911NF-14-1-0520 US Army of USA, Fondecyt Regular, CEX2018-000792-M Unidad de Excelencia María de Maeztu
Alessandri-Haber,
A transient receptor potential vanilloid 4-dependent mechanism of hyperalgesia is engaged by concerted action of inflammatory mediators.
2006, Pubmed
Alessandri-Haber,
A transient receptor potential vanilloid 4-dependent mechanism of hyperalgesia is engaged by concerted action of inflammatory mediators.
2006,
Pubmed
Alexander,
THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels.
2019,
Pubmed
Alpizar,
TRPV4 activation triggers protective responses to bacterial lipopolysaccharides in airway epithelial cells.
2017,
Pubmed
Andrade,
TRPV4 channel is involved in the coupling of fluid viscosity changes to epithelial ciliary activity.
2005,
Pubmed
Arniges,
Swelling-activated Ca2+ entry via TRPV4 channel is defective in cystic fibrosis airway epithelia.
2004,
Pubmed
Atobe,
Discovery of Novel Transient Receptor Potential Vanilloid 4 (TRPV4) Agonists as Regulators of Chondrogenic Differentiation: Identification of Quinazolin-4(3 H)-ones and in Vivo Studies on a Surgically Induced Rat Model of Osteoarthritis.
2019,
Pubmed
Bai,
Structural basis for pharmacological modulation of the TRPC6 channel.
2020,
Pubmed
Berna-Erro,
Structural determinants of 5',6'-epoxyeicosatrienoic acid binding to and activation of TRPV4 channel.
2017,
Pubmed
Brnardic,
Discovery of Pyrrolidine Sulfonamides as Selective and Orally Bioavailable Antagonists of Transient Receptor Potential Vanilloid-4 (TRPV4).
2018,
Pubmed
Cao,
TRPV1 structures in distinct conformations reveal activation mechanisms.
2013,
Pubmed
Carlson,
Developing a dynamic pharmacophore model for HIV-1 integrase.
2000,
Pubmed
Caterina,
The capsaicin receptor: a heat-activated ion channel in the pain pathway.
1997,
Pubmed
,
Xenbase
Cheung,
Discovery of GSK2193874: An Orally Active, Potent, and Selective Blocker of Transient Receptor Potential Vanilloid 4.
2017,
Pubmed
Deng,
Cryo-EM and X-ray structures of TRPV4 reveal insight into ion permeation and gating mechanisms.
2018,
Pubmed
,
Xenbase
Doñate-Macián,
The TRPV4 channel links calcium influx to DDX3X activity and viral infectivity.
2018,
Pubmed
Everaerts,
Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis.
2010,
Pubmed
Fernandes,
IP3 sensitizes TRPV4 channel to the mechano- and osmotransducing messenger 5'-6'-epoxyeicosatrienoic acid.
2008,
Pubmed
Fernández-Fernández,
Functional coupling of TRPV4 cationic channel and large conductance, calcium-dependent potassium channel in human bronchial epithelial cell lines.
2008,
Pubmed
Friesner,
Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes.
2006,
Pubmed
Galindo-Villegas,
TRPV4-Mediated Detection of Hyposmotic Stress by Skin Keratinocytes Activates Developmental Immunity.
2016,
Pubmed
Gao,
TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action.
2016,
Pubmed
Garcia-Elias,
Interaction between the Linker, Pre-S1, and TRP Domains Determines Folding, Assembly, and Trafficking of TRPV Channels.
2015,
Pubmed
Garcia-Elias,
Phosphatidylinositol-4,5-biphosphate-dependent rearrangement of TRPV4 cytosolic tails enables channel activation by physiological stimuli.
2013,
Pubmed
Gevaert,
Deletion of the transient receptor potential cation channel TRPV4 impairs murine bladder voiding.
2007,
Pubmed
Goyal,
Clinical Pharmacokinetics, Safety, and Tolerability of a Novel, First-in-Class TRPV4 Ion Channel Inhibitor, GSK2798745, in Healthy and Heart Failure Subjects.
2019,
Pubmed
Greenidge,
MM/GBSA binding energy prediction on the PDBbind data set: successes, failures, and directions for further improvement.
2013,
Pubmed
Güler,
Heat-evoked activation of the ion channel, TRPV4.
2002,
Pubmed
,
Xenbase
Jung,
Functional coupling of GABAA/B receptors and the channel TRPV4 mediates rapid progesterone signaling in the oviduct.
2018,
Pubmed
Liao,
Structure of the TRPV1 ion channel determined by electron cryo-microscopy.
2013,
Pubmed
Liedtke,
Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor.
2000,
Pubmed
Liedtke,
Abnormal osmotic regulation in trpv4-/- mice.
2003,
Pubmed
Lorenzo,
TRPV4 channel participates in receptor-operated calcium entry and ciliary beat frequency regulation in mouse airway epithelial cells.
2008,
Pubmed
Moore,
UVB radiation generates sunburn pain and affects skin by activating epidermal TRPV4 ion channels and triggering endothelin-1 signaling.
2013,
Pubmed
Muramatsu,
Functional gene screening system identified TRPV4 as a regulator of chondrogenic differentiation.
2007,
Pubmed
Nilius,
The puzzle of TRPV4 channelopathies.
2013,
Pubmed
O'Conor,
TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading.
2014,
Pubmed
Rahaman,
TRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in mice.
2014,
Pubmed
Shao,
Curcumin Induces Endothelium-Dependent Relaxation by Activating Endothelial TRPV4 Channels.
2019,
Pubmed
Singh,
Structural bases of TRP channel TRPV6 allosteric modulation by 2-APB.
2018,
Pubmed
Smith,
Bisandrographolide from Andrographis paniculata activates TRPV4 channels.
2006,
Pubmed
Strotmann,
OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity.
2000,
Pubmed
Takayama,
Modulation of water efflux through functional interaction between TRPV4 and TMEM16A/anoctamin 1.
2014,
Pubmed
Thorneloe,
N-((1S)-1-{[4-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-1-piperazinyl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide (GSK1016790A), a novel and potent transient receptor potential vanilloid 4 channel agonist induces urinary bladder contraction and hyperactivity: Part I.
2008,
Pubmed
Tian,
A loss-of-function nonsynonymous polymorphism in the osmoregulatory TRPV4 gene is associated with human hyponatremia.
2009,
Pubmed
Vamathevan,
Applications of machine learning in drug discovery and development.
2019,
Pubmed
Vincent,
Identification and characterization of novel TRPV4 modulators.
2009,
Pubmed
,
Xenbase
Voets,
Molecular determinants of permeation through the cation channel TRPV4.
2002,
Pubmed
Vriens,
Modulation of the Ca2 permeable cation channel TRPV4 by cytochrome P450 epoxygenases in vascular endothelium.
2005,
Pubmed
Vriens,
Determinants of 4 alpha-phorbol sensitivity in transmembrane domains 3 and 4 of the cation channel TRPV4.
2007,
Pubmed
Vriens,
Cell swelling, heat, and chemical agonists use distinct pathways for the activation of the cation channel TRPV4.
2004,
Pubmed
Watanabe,
Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives.
2002,
Pubmed
Watanabe,
Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels.
2003,
Pubmed
Watanabe,
Heat-evoked activation of TRPV4 channels in a HEK293 cell expression system and in native mouse aorta endothelial cells.
2002,
Pubmed
Yang,
Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.
2015,
Pubmed
Yin,
Structural basis of cooling agent and lipid sensing by the cold-activated TRPM8 channel.
2019,
Pubmed
Zhang,
Morin induces endothelium-dependent relaxation by activating TRPV4 channels in rat mesenteric arteries.
2019,
Pubmed
Zhao,
The Cep63 paralogue Deup1 enables massive de novo centriole biogenesis for vertebrate multiciliogenesis.
2013,
Pubmed
,
Xenbase
Zhu,
Association of TRPV4 gene polymorphisms with chronic obstructive pulmonary disease.
2009,
Pubmed
