: ATP2B1 is a known regulator of calcium (Ca2+) 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.
Targeting ATP2B1 impairs PI3K/Akt/FOXO signaling and reduces SARS-COV-2 infection and replication / de Antonellis, P.; Ferrucci, V.; Miceli, M.; Bibbo, F.; Asadzadeh, F.; Gorini, F.; Mattivi, A.; Boccia, A.; Russo, R.; Andolfo, I.; Lasorsa, V. A.; Cantalupo, S.; Fusco, G.; Viscardi, M.; Brandi, S.; Cerino, P.; Monaco, V.; Choi, D. -R.; Cheong, J. -H.; Iolascon, A.; Amente, S.; Monti, M.; Fava, L. L.; Capasso, M.; Kim, H. -Y.; Zollo, M.. - In: EMBO REPORTS. - ISSN 1469-3178. - 25:7(2024), pp. 2974-3007. [10.1038/s44319-024-00164-z]
Targeting ATP2B1 impairs PI3K/Akt/FOXO signaling and reduces SARS-COV-2 infection and replication
de Antonellis P.;Ferrucci V.;Asadzadeh F.;Gorini F.;Russo R.;Andolfo I.;Lasorsa V. A.;Cantalupo S.;Fusco G.;Viscardi M.;Brandi S.;Cerino P.;Monaco V.;Iolascon A.;Amente S.;Monti M.;Capasso M.;Zollo M.
2024
Abstract
: ATP2B1 is a known regulator of calcium (Ca2+) 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
