A screening campaign in sea urchin egg homogenate as a platform for discovering modulators of NAADP-dependent Ca2+ signaling in human cells.
Identifieur interne : 000800 ( PubMed/Curation ); précédent : 000799; suivant : 000801A 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.
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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<term>Cell Line</term>
<term>Drug Evaluation, Preclinical</term>
<term>Humans</term>
<term>Lysosomes (drug effects)</term>
<term>Lysosomes (metabolism)</term>
<term>NADP (analogs & derivatives)</term>
<term>NADP (pharmacology)</term>
<term>Ovum (drug effects)</term>
<term>Ovum (metabolism)</term>
<term>Reproducibility of Results</term>
<term>Sea Urchins (drug effects)</term>
<term>Sea Urchins (metabolism)</term>
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<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term>
<term>Calcium (métabolisme)</term>
<term>Echinoidea ()</term>
<term>Echinoidea (métabolisme)</term>
<term>Humains</term>
<term>Lignée cellulaire</term>
<term>Lysosomes ()</term>
<term>Lysosomes (métabolisme)</term>
<term>NADP (analogues et dérivés)</term>
<term>NADP (pharmacologie)</term>
<term>Ovule ()</term>
<term>Ovule (métabolisme)</term>
<term>Reproductibilité des résultats</term>
<term>Signalisation du calcium ()</term>
<term>Évaluation préclinique de médicament</term>
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<term>Lysosomes</term>
<term>Ovum</term>
<term>Sea Urchins</term>
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<term>Ovum</term>
<term>Sea Urchins</term>
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<term>Ovule</term>
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<term>Reproducibility of Results</term>
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<term>Lignée cellulaire</term>
<term>Lysosomes</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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<Month>06</Month>
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<Title>Cell calcium</Title>
<ISOAbbreviation>Cell Calcium</ISOAbbreviation>
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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>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Gunaratne</LastName>
<ForeName>Gihan S</ForeName>
<Initials>GS</Initials>
<AffiliationInfo><Affiliation>Department of Pharmacology, University of Minnesota Medical School, MN 55455, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Johns</LastName>
<ForeName>Malcolm E</ForeName>
<Initials>ME</Initials>
<AffiliationInfo><Affiliation>Department of Pharmacology, University of Minnesota Medical School, MN 55455, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Hintz</LastName>
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<Initials>HM</Initials>
<AffiliationInfo><Affiliation>Department of Pharmacology, University of Minnesota Medical School, MN 55455, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Walseth</LastName>
<ForeName>Timothy F</ForeName>
<Initials>TF</Initials>
<AffiliationInfo><Affiliation>Department of Pharmacology, University of Minnesota Medical School, MN 55455, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Marchant</LastName>
<ForeName>Jonathan S</ForeName>
<Initials>JS</Initials>
<AffiliationInfo><Affiliation>Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee WI 53226, USA. Electronic address: JMarchant@mcw.edu.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<GrantList CompleteYN="Y"><Grant><GrantID>R01 GM088790</GrantID>
<Acronym>GM</Acronym>
<Agency>NIGMS NIH HHS</Agency>
<Country>United States</Country>
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<MedlineTA>Cell Calcium</MedlineTA>
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<MeshHeading><DescriptorName UI="D020013" MajorTopicYN="N">Calcium Signaling</DescriptorName>
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<MeshHeading><DescriptorName UI="D002460" MajorTopicYN="N">Cell Line</DescriptorName>
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<MeshHeading><DescriptorName UI="D004353" MajorTopicYN="N">Drug Evaluation, Preclinical</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008247" MajorTopicYN="N">Lysosomes</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D009249" MajorTopicYN="N">NADP</DescriptorName>
<QualifierName UI="Q000031" MajorTopicYN="Y">analogs & derivatives</QualifierName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D010063" MajorTopicYN="N">Ovum</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D015203" MajorTopicYN="N">Reproducibility of Results</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D012617" MajorTopicYN="N">Sea Urchins</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
</MeshHeading>
</MeshHeadingList>
<KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y">Ca(2+)release</Keyword>
<Keyword MajorTopicYN="Y">Drug screening</Keyword>
<Keyword MajorTopicYN="Y">Endosomes</Keyword>
<Keyword MajorTopicYN="Y">Lysosomes</Keyword>
<Keyword MajorTopicYN="Y">NAADP</Keyword>
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