A screening campaign in sea urchin egg homogenate as a platform for discovering modulators of NAADP-dependent Ca2+ signaling in human cells.
Identifieur interne : 000A81 ( Main/Exploration ); précédent : 000A80; suivant : 000A82A 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
Affiliations:
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Gunaratne</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pharmacology, University of Minnesota Medical School, MN 55455, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pharmacology, University of Minnesota Medical School, MN 55455</wicri:regionArea><placeName><region type="state">Minnesota</region></placeName></affiliation></author><author><name sortKey="Johns, Malcolm E" sort="Johns, Malcolm E" uniqKey="Johns M" first="Malcolm E" last="Johns">Malcolm E. 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Hintz</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pharmacology, University of Minnesota Medical School, MN 55455, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pharmacology, University of Minnesota Medical School, MN 55455</wicri:regionArea><placeName><region type="state">Minnesota</region></placeName></affiliation></author><author><name sortKey="Walseth, Timothy F" sort="Walseth, Timothy F" uniqKey="Walseth T" first="Timothy F" last="Walseth">Timothy F. 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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></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Minnesota</li></region></list><tree><country name="États-Unis"><region name="Minnesota"><name sortKey="Gunaratne, Gihan S" sort="Gunaratne, Gihan S" uniqKey="Gunaratne G" first="Gihan S" last="Gunaratne">Gihan S. Gunaratne</name></region><name sortKey="Hintz, Hallie M" sort="Hintz, Hallie M" uniqKey="Hintz H" first="Hallie M" last="Hintz">Hallie M. Hintz</name><name sortKey="Johns, Malcolm E" sort="Johns, Malcolm E" uniqKey="Johns M" first="Malcolm E" last="Johns">Malcolm E. Johns</name><name sortKey="Marchant, Jonathan S" sort="Marchant, Jonathan S" uniqKey="Marchant J" first="Jonathan S" last="Marchant">Jonathan S. Marchant</name><name sortKey="Walseth, Timothy F" sort="Walseth, Timothy F" uniqKey="Walseth T" first="Timothy F" last="Walseth">Timothy F. Walseth</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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