1. Targeting ATP2B1 impairs PI3K/Akt/FOXO signaling and reduces SARS-COV-2 infection and replication.
- Author
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de Antonellis P, Ferrucci V, Miceli M, Bibbo F, Asadzadeh F, Gorini F, Mattivi A, Boccia A, Russo R, Andolfo I, Lasorsa VA, Cantalupo S, Fusco G, Viscardi M, Brandi S, Cerino P, Monaco V, Choi DR, Cheong JH, Iolascon A, Amente S, Monti M, Fava LL, Capasso M, Kim HY, and Zollo M
- Subjects
- Humans, Animals, Forkhead Box Protein O3 metabolism, Forkhead Box Protein O3 genetics, Chlorocebus aethiops, COVID-19 Drug Treatment, Vero Cells, Female, Calcium-Transporting ATPases metabolism, Calcium-Transporting ATPases genetics, Male, SARS-CoV-2 drug effects, SARS-CoV-2 physiology, Virus Replication drug effects, Proto-Oncogene Proteins c-akt metabolism, COVID-19 virology, COVID-19 metabolism, Signal Transduction drug effects, Phosphatidylinositol 3-Kinases metabolism, Calcium metabolism
- Abstract
ATP2B1 is a known regulator of calcium (Ca
2+ ) cellular export and homeostasis. Diminished levels of intracellular Ca2+ content have been suggested to impair SARS-CoV-2 replication. Here, we demonstrate that a nontoxic caloxin-derivative compound (PI-7) reduces intracellular Ca2+ levels and impairs SARS-CoV-2 infection. Furthermore, a rare homozygous intronic variant of ATP2B1 is shown to be associated with the severity of COVID-19. The mechanism of action during SARS-CoV-2 infection involves the PI3K/Akt signaling pathway activation, inactivation of FOXO3 transcription factor function, and subsequent transcriptional inhibition of the membrane and reticulum Ca2+ pumps ATP2B1 and ATP2A1, respectively. The pharmacological action of compound PI-7 on sustaining both ATP2B1 and ATP2A1 expression reduces the intracellular cytoplasmic Ca2+ pool and thus negatively influences SARS-CoV-2 replication and propagation. As compound PI-7 lacks toxicity in vitro, its prophylactic use as a therapeutic agent against COVID-19 is envisioned here., (© 2024. The Author(s).)- Published
- 2024
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