Niemann-Pick C1 protein (NPC1) (NPC1)

Niemann-Pick C1 (NPC1) is a 1278-amino acid multi-pass transmembrane protein primarily localized to the late endosome and lysosome membranes (UniProt: O15118). Its physiological function involves the transport of unesterified cholesterol from the lysosomal lumen to the cytosol, a process essential for maintaining cellular lipid homeostasis (PubMed: 9216744). Beyond its metabolic role, NPC1 is the definitive intracellular receptor for filoviruses such as Ebola virus (EBOV) and Sudan virus (SUDV) (PubMed: 21866103). The viral entry mechanism requires host cathepsins to cleave the viral glycoprotein (GP) into a primed form (GPcl), which then binds specifically to the luminal C domain (Domain C) of NPC1 (PubMed: 26018892). This binding triggers the fusion of the viral and endosomal membranes, facilitating the release of the viral genome into the host cytoplasm (PubMed: 27239043). Mutations in NPC1 result in Niemann-Pick disease type C1, a progressive and fatal neurodegenerative disorder characterized by the toxic accumulation of lipids (NIH: Genetic and Rare Diseases Information Center). Because NPC1 is essential for viral infection, it is a target for small-molecule inhibitors and antibodies designed to block viral entry, though such strategies must avoid disrupting its critical role in cholesterol transport (PubMed: 22301556).

Other names

NPC1Niemann-Pick disease type C1 proteinNPC1 C domainNiemann-Pick C1 C domain

Drugs targeting NPC1 for antiviral purposes typically function as entry inhibitors by sterically hindering the interaction between the NPC1 C domain and the cleaved viral glycoprotein (GPcl), thereby preventing viral-endosomal membrane fusion (PubMed: 30104373). In the context of Niemann-Pick disease, pharmacological chaperones or substrate reduction therapies like miglustat are used to manage lipid accumulation (PubMed: 19652107).