Marburg virus glycoprotein - Niemann-Pick C1 receptor binding site (MARV GP-NPC1 RBS)

The Marburg virus glycoprotein (MARV GP) - Niemann-Pick C1 (NPC1) receptor binding site is a critical molecular junction required for the entry of Marburg virus into host cells. The viral GP is a trimeric surface protein that, upon internalization into host endosomes, undergoes proteolytic processing by host cathepsins to remove the glycan cap and mucin-like domain, thereby exposing the receptor binding site (RBS) on the GP1 subunit (Hashiguchi et al., 2015, Cell). This exposed RBS specifically binds to the luminal domain C of NPC1, a host intracellular cholesterol transporter that serves as an obligatory entry receptor for all known filoviruses (Carette et al., 2011, Nature; Ng et al., 2012, eLife). This binding event is the prerequisite for the subsequent conformational changes in the GP2 subunit that drive the fusion of viral and endosomal membranes. Because the GP-NPC1 interaction is a conserved and mandatory step in the viral life cycle, it represents a high-priority target for the development of antiviral therapies, such as monoclonal antibodies (e.g., MR191) and small-molecule inhibitors designed to block viral attachment and entry (King et al., 2018, Cell Reports). Targeting this site aims to block the viral entry process, thereby preventing the progression of Marburg virus disease, a severe and often fatal hemorrhagic fever.

Other names

Marburg marburgvirus glycoprotein - NPC1 receptor binding siteMARV GP-NPC1 interfaceMarburg virus GP receptor binding domainMARV GP1-NPC1 binding siteMarburg virus glycoprotein RBS

The mechanism of action involves the competitive or steric inhibition of the binding between the primed (cathepsin-cleaved) Marburg virus glycoprotein 1 (GP1) subunit and the second luminal domain (Domain C) of the host Niemann-Pick C1 (NPC1) receptor. By preventing this interaction, the drug blocks the subsequent GP2-mediated membrane fusion, thereby halting the entry of the viral ribonucleoprotein into the host cell cytoplasm (Hashiguchi et al., 2015, Cell; Ng et al., 2012, eLife).