Flavivirus envelope protein fusion loop (E-FL) (E-FL)

The Flavivirus envelope (E) protein fusion loop is a highly conserved, hydrophobic peptide sequence located at the tip of domain II (DII) of the viral E protein (Rey et al., 1995, Nature). It is essential for the infection process of various flaviviruses, including Dengue, Zika, and West Nile viruses, by mediating the fusion between the viral envelope and the host endosomal membrane (Pierson & Kielian, 2013, Virology). Upon exposure to the acidic environment of the endosome, the E protein undergoes a structural transition from a metastable dimer to a stable trimer, which projects the fusion loop toward the host membrane for insertion (Stiasny et al., 2006, J Virol). Due to its high degree of sequence conservation across the Flavivirus genus, the fusion loop is a major target for broadly neutralizing antibodies (bnAbs) and potential small-molecule fusion inhibitors. However, a significant challenge in targeting this site is the risk of antibody-dependent enhancement (ADE), where non-neutralizing or sub-neutralizing antibodies against the fusion loop can promote viral uptake into myeloid cells via Fc receptors (Dejnirattisai et al., 2010, Science). This phenomenon can lead to increased viral load and more severe clinical manifestations, such as Dengue Hemorrhagic Fever. Consequently, therapeutic strategies must focus on achieving high-affinity binding or engineering antibody Fc regions to minimize ADE risks. The fusion loop remains a focal point for structure-based vaccine design aiming to elicit protective, rather than sensitizing, immune responses.

Other names

E-DII fusion loopFlavivirus fusion peptidecd loop of domain IIConserved fusion loop (CFL)

Neutralization of viral infectivity by blocking the insertion of the fusion loop into the host endosomal membrane or preventing the E protein conformational change required for fusion.