Of importance, using artificial intelligence screening, we identify a new nontoxic caloxin-derivative compound (PI-7) that: (i) promotes ATP2B1 activity as measured by the reduction of intracellular cellular Ca2+ levels, (ii) enhances ATP2B1 and ATP2A1 mRNA and protein levels via FOXO3 transcriptional regulation, (iii) impairs SARS- CoV-2 (VOCs: Delta and Omicron 2 and 5) infection and propagation by negatively affecting the generation of syncytia, and (iv) prevents the release of inflammatory cytokines that are targets of the NF-κB signaling pathway. This evidence concerns the gene ATP2B1 and infection.