Envelope (E) viroporin protein, ORF5, of 75 aas and 1 N-terminal TMS. The E-proteins of CoV, CoV-2 and MERS oligomerize to form homopentamers by aligning their TMSs into a pore-forming complex in phospholipid membranes (Surya et al. 2015). The pore is weakly cation selective with Ca²⁺ favored over K⁺, and Na⁺ favored over H⁺ (Castaño-Rodriguez et al. 2018). It is involved in various aspects of the virus life cycle including assembly, budding, envelope formation, virus release, and inflammasome activation (Breitinger et al. 2021). The structure and drug binding of the SARS-CoV-2 Envelope (E) protein in phospholipid bilayers has been determined (Hong et al. 2020). E forms a five-helix bundle surrounding a narrow central pore. The middle of the TM segment is distorted from the ideal α-helical geometry due to three regularly spaced phenylalanine residues, which stack within each helix and between neighboring helices. These aromatic interactions, together with interhelical Val and Leu interdigitation, cause a dehydrated pore compared to the viroporins of influenza and HIV viruses. Hexamethylene amiloride and amantadine bind shallowly to polar residues at the N-terminal lumen, while acidic pH affects the C-terminal conformation. Thus, SARS-CoV-2 E forms a structurally robust but bipartite channel whose N- and C-terminal halves can interact with drugs, ions and other viral and host proteins semi-independently (Hong et al. 2020). Mandala et al. 2020 reported a 2.1-Å structure and the drug-binding site of E's transmembrane domain (ETM), determined using solid-state NMR spectroscopy. In lipid bilayers that mimic the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) membrane, ETM forms a five-helix bundle surrounding a narrow pore. The protein deviates from the ideal alpha-helical geometry due to three phenylalanine residues, which stack within each helix and between helices. Together with valine and leucine interdigitation, these cause a dehydrated pore compared with the viroporins of influenza viruses and HIV. Hexamethylene amiloride binds the polar amino-terminal lumen, whereas acidic pH affects the carboxy-terminal conformation. Thus, the N- and C-terminal halves of this bipartite channel may interact with other viral and host proteins semi-independently. The structure sets the stage for designing E inhibitors as antiviral drugs (Mandala et al. 2020). Chenodeoxycholate(CDC) and ursodeoxycholate (UDC) bind to the envelope (E) protein of SARS-Cov2 and serve as candidates to hinder the survival of SARS-Cov2 by disrupting the structure of SARS-Cov2-E and facilitating the entry of solvents/polar inhibitors inside the viral cell (Yadav et al. 2022). Interactions of SARS-CoV-2 envelope protein with amilorides promote antiviral activity (Park et al. 2021). E-protein mediated currents were inhibited by amantadine and rimantadine, as well as 5-(N,N-hexamethylene)amiloride (HMA). Of 10 flavonoids, epigallocatechin and quercetin were most effective (Breitinger et al. 2021). The e-protein increases the intra-Golgi pH by forming a cation channel that is regulated by pH(Cabrera-Garcia et al. 2021). A cell-based system combined with flow cytometry has been used to evaluate antibody responses against SARS-CoV-2 transmembrane proteins in patients with COVID-19 (Martin et al. 2022). An intricate aromatic network regulates the opening of the ETM channel pore (Medeiros-Silva et al. 2022). Rotational dynamics of the transmembrane domains play important roles in peptide dynamics of viral fusion and ion channel forming proteins (Wang and Fischer 2022). Hexamethylene amiloride derivatives are potential luminal inhibitors of the SARS-CoV-2 E Protein (Jalily et al. 2022). The envelope proteins from SARS-CoV-2 and SARS-CoV potently reduce the infectivity of human immunodeficiency virus type 1 (HIV-1) (Henke et al. 2022). The cytoplasmic domain of the SARS-CoV-2 envelope protein assembles into a beta-sheet bundle in lipid bilayers (Dregni et al. 2023). The E protein of SARS-CoV-2 efficiently down-regulates the cell surface expression of the antigen-presenting molecule, CD1d, to suppress the function of iNKT cells. E protein  plays roles in virion packaging and envelopment during viral morphogenesis. The transmembrane domain of E protein is responsible for suppressing CD1d expression by specifically reducing the level of mature, post-ER forms of CD1d, suggesting that it suppressed the trafficking of CD1d proteins and leads to their degradation. Point mutations demonstrated that the putative ion channel function is required for suppression of CD1d expression, and inhibition of the ion channel function using small chemicals rescued CD1d expression (Lu et al. 2023). However, Zhang et al. 2023 identified a symmetric helix-helix interface, leading to the prediction of a dimeric structure that does not support channel activity. The two helices have a tilt angle of only 6 degrees , resulting in an extended interface dominated by Leu and Val side chains. While residues Val14-Thr35 are almost all buried in the hydrophobic region of the membrane, Asn15 lines a water-filled pocket that potentially serves as a drug-binding site. The E and other viral proteins may adopt different oligomeric states to help perform multiple functions (Zhang et al. 2023).