| Autor: |
Gihan S, Gunaratne, Malcolm E, Johns, Hallie M, Hintz, Timothy F, Walseth, Jonathan S, Marchant |
| Rok vydání: |
2018 |
| Předmět: |
|
| Zdroj: |
Cell calcium. 75 |
| ISSN: |
1532-1991 |
| Popis: |
The Ca(2+) 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(2+) 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(2+) 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(2+) release (but not cADPR- or IP(3)-evoked Ca(2+) 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(2+) release. A validation pipeline for these candidates yielded seven drugs that inhibited NAADP-evoked Ca(2+) release without depleting acidic Ca(2+) 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(2+) 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(3)-dependent Ca(2+) signaling with potential therapeutic value. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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