Orf3a of 275 aas and 3 central TMSs. Orf3a forms homodimers and homotetramers and is a non-selective catioin channel that is blocked by polycation channel inhibitors (Kern et al. 2021). They carry a PDZ-binding domain, lending them the versatility to interact with more than 400 target proteins in infected host cells. Structural considerations have been discussed (Barrantes 2021). Naturally occurring mutations in ORF3a are common and have been analyzed, and 28 fully concerved residues in 70,000 sequences that probably have structural or functional roles were also identified (Bianchi et al. 2020). Viroporin 3a exhibits allosteric properties (Tee et al. 2021). It has been implicated in apoptosis and inhibition of autophagy. The structure of the dimer has been determined at 2.1 Å resolution by cryoEM (Kern et al. 2021). Pentamidine is a channel blocker of Orf3a (Zhang et al. 2022). ORF3a is inhibited by adamantanes and phenolic plant metabolites (Fam et al. 2023). SARS-CoV-2 ORF3A interacts with the Clic-like chloride channel-1 (CLCC1; TC# 1.A.36.1.1) and triggers an unfolded protein response (Gruner et al. 2023).  SARS-CoV-2 and its ORF3a, E and M viroporins activate inflammasome in human macrophages (Ambrożek-Latecka et al. 2024). SARS-CoV-2 ORF3a positively regulates NF-κB activity by enhancing IKKβ-NEMO interaction (Nie et al. 2023).  ORF3a is a lysosomal water-permeable channel, essential for lysosome deacidification and inactivation, key steps to promote virus egress (Michelucci et al. 2025). Thus, ORF3a is a lysosomal water-permeable channel, essential for lysosome deacidification and inactivation, key steps to promote virus egress.