MersV1, Ncbi, Merge, bibRecord, 001F42

A screening campaign in sea urchin egg homogenate as a platform for discovering modulators of NAADP-dependent Ca2+ signaling in human cells.

Identifieur interne : 001F42 ( Ncbi/Merge ); précédent : 001F41; suivant : 001F43

A screening campaign in sea urchin egg homogenate as a platform for discovering modulators of NAADP-dependent Ca2+ signaling in human cells.

Auteurs : Gihan S. Gunaratne [États-Unis] ; Malcolm E. Johns [États-Unis] ; Hallie M. Hintz [États-Unis] ; Timothy F. Walseth [États-Unis] ; Jonathan S. Marchant [États-Unis]

Source :

Cell calcium [ 1532-1991 ] ; 2018.

RBID : pubmed:30145428

Descripteurs français

KwdFr :
- Animaux, Calcium (métabolisme), Echinoidea (), Echinoidea (métabolisme), Humains, Lignée cellulaire, Lysosomes (), Lysosomes (métabolisme), NADP (analogues et dérivés), NADP (pharmacologie), Ovule (), Ovule (métabolisme), Reproductibilité des résultats, Signalisation du calcium (), Évaluation préclinique de médicament.
MESH :
- analogues et dérivés : NADP.
- métabolisme : Calcium, Echinoidea, Lysosomes, Ovule.
- pharmacologie : NADP.
- Animaux, Echinoidea, Humains, Lignée cellulaire, Lysosomes, Ovule, Reproductibilité des résultats, Signalisation du calcium, Évaluation préclinique de médicament.

English descriptors

KwdEn :
- Animals, Calcium (metabolism), Calcium Signaling (drug effects), Cell Line, Drug Evaluation, Preclinical, Humans, Lysosomes (drug effects), Lysosomes (metabolism), NADP (analogs & derivatives), NADP (pharmacology), Ovum (drug effects), Ovum (metabolism), Reproducibility of Results, Sea Urchins (drug effects), Sea Urchins (metabolism).
MESH :
- chemical , analogs & derivatives : NADP.
- chemical , metabolism : Calcium.
- drug effects : Calcium Signaling, Lysosomes, Ovum, Sea Urchins.
- metabolism : Lysosomes, Ovum, Sea Urchins.
- chemical , pharmacology : NADP.
- Animals, Cell Line, Drug Evaluation, Preclinical, Humans, Reproducibility of Results.

Abstract

The Ca²⁺ mobilizing second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) regulates intracellular trafficking events, including translocation of certain enveloped viruses through the endolysosomal system. Targeting NAADP-evoked Ca²⁺ signaling may therefore be an effective strategy for discovering novel antivirals as well as therapeutics for other disorders. To aid discovery of novel scaffolds that modulate NAADP-evoked Ca²⁺ signaling in human cells, we have investigated the potential of using the sea urchin egg homogenate system for a screening campaign. Known pharmacological inhibitors of NAADP-evoked Ca²⁺ release (but not cADPR- or IP₃-evoked Ca²⁺ release) in this invertebrate system strongly correlated with inhibition of MERS-pseudovirus infectivity in a human cell line. A primary screen of 1534 compounds yielded eighteen 'hits' exhibiting >80% inhibition of NAADP-evoked Ca²⁺ release. A validation pipeline for these candidates yielded seven drugs that inhibited NAADP-evoked Ca²⁺ release without depleting acidic Ca²⁺ stores in a human cell line. These candidates displayed a similar penetrance of inhibition in both the sea urchin system and the human cell line, and the extent of inhibition of NAADP-evoked Ca²⁺ signals correlated well with observed inhibition of infectivity of a Middle East Respiratory syndrome coronavirus (MERS-CoV) pseudovirus. These experiments support the potential of this simple, homogenate system for screening campaigns to discover modulators of NAADP, cADPR and IP₃-dependent Ca²⁺ signaling with potential therapeutic value.

DOI: 10.1016/j.ceca.2018.08.002
PubMed: 30145428

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Le document en format XML

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<term>Reproducibility of Results</term>
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<term>Humains</term>
<term>Lignée cellulaire</term>
<term>Lysosomes</term>
<term>Ovule</term>
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<front><div type="abstract" xml:lang="en">The Ca<sup>2+</sup>
 mobilizing second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) regulates intracellular trafficking events, including translocation of certain enveloped viruses through the endolysosomal system. Targeting NAADP-evoked Ca<sup>2+</sup>
 signaling may therefore be an effective strategy for discovering novel antivirals as well as therapeutics for other disorders. To aid discovery of novel scaffolds that modulate NAADP-evoked Ca<sup>2+</sup>
 signaling in human cells, we have investigated the potential of using the sea urchin egg homogenate system for a screening campaign. Known pharmacological inhibitors of NAADP-evoked Ca<sup>2+</sup>
 release (but not cADPR- or IP<sub>3</sub>
-evoked Ca<sup>2+</sup>
 release) in this invertebrate system strongly correlated with inhibition of MERS-pseudovirus infectivity in a human cell line. A primary screen of 1534 compounds yielded eighteen 'hits' exhibiting >80% inhibition of NAADP-evoked Ca<sup>2+</sup>
 release. A validation pipeline for these candidates yielded seven drugs that inhibited NAADP-evoked Ca<sup>2+</sup>
 release without depleting acidic Ca<sup>2+</sup>
 stores in a human cell line. These candidates displayed a similar penetrance of inhibition in both the sea urchin system and the human cell line, and the extent of inhibition of NAADP-evoked Ca<sup>2+</sup>
 signals correlated well with observed inhibition of infectivity of a Middle East Respiratory syndrome coronavirus (MERS-CoV) pseudovirus. These experiments support the potential of this simple, homogenate system for screening campaigns to discover modulators of NAADP, cADPR and IP<sub>3</sub>
-dependent Ca<sup>2+</sup>
 signaling with potential therapeutic value.</div>
</front>
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<ArticleTitle>A screening campaign in sea urchin egg homogenate as a platform for discovering modulators of NAADP-dependent Ca<sup>2+</sup>
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<Abstract><AbstractText>The Ca<sup>2+</sup>
 mobilizing second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) regulates intracellular trafficking events, including translocation of certain enveloped viruses through the endolysosomal system. Targeting NAADP-evoked Ca<sup>2+</sup>
 signaling may therefore be an effective strategy for discovering novel antivirals as well as therapeutics for other disorders. To aid discovery of novel scaffolds that modulate NAADP-evoked Ca<sup>2+</sup>
 signaling in human cells, we have investigated the potential of using the sea urchin egg homogenate system for a screening campaign. Known pharmacological inhibitors of NAADP-evoked Ca<sup>2+</sup>
 release (but not cADPR- or IP<sub>3</sub>
-evoked Ca<sup>2+</sup>
 release) in this invertebrate system strongly correlated with inhibition of MERS-pseudovirus infectivity in a human cell line. A primary screen of 1534 compounds yielded eighteen 'hits' exhibiting >80% inhibition of NAADP-evoked Ca<sup>2+</sup>
 release. A validation pipeline for these candidates yielded seven drugs that inhibited NAADP-evoked Ca<sup>2+</sup>
 release without depleting acidic Ca<sup>2+</sup>
 stores in a human cell line. These candidates displayed a similar penetrance of inhibition in both the sea urchin system and the human cell line, and the extent of inhibition of NAADP-evoked Ca<sup>2+</sup>
 signals correlated well with observed inhibition of infectivity of a Middle East Respiratory syndrome coronavirus (MERS-CoV) pseudovirus. These experiments support the potential of this simple, homogenate system for screening campaigns to discover modulators of NAADP, cADPR and IP<sub>3</sub>
-dependent Ca<sup>2+</sup>
 signaling with potential therapeutic value.</AbstractText>
<CopyrightInformation>Copyright © 2018 Elsevier Ltd. All rights reserved.</CopyrightInformation>
</Abstract>
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<ForeName>Gihan S</ForeName>
<Initials>GS</Initials>
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<MeshHeading><DescriptorName UI="D010063" MajorTopicYN="N">Ovum</DescriptorName>
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<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
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A screening campaign in sea urchin egg homogenate as a platform for discovering modulators of NAADP-dependent Ca2+ signaling in human cells.

A screening campaign in sea urchin egg homogenate as a platform for discovering modulators of NAADP-dependent Ca2+ signaling in human cells.

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