Small molecule targets Env for endoplasmic reticulum-associated protein degradation and inhibits human immunodeficiency virus type 1 propagation.
Human immunodeficiency virus type 1 (HIV-1) is dependent on its envelope glycoprotein (Env) to bind, fuse, and subsequently infect a cell. We show here that treatment of HIV-1-infected cells with glycyl-prolyl-glycine amide (GPG-NH(2)), dramatically reduced the infectivity of the released viral particles by decreasing their Env incorporation. The mechanism of GPG-NH(2) was uncovered by examining Env expression and maturation in treated cells. GPG-NH(2) treatment was found to affect Env by significantly decreasing its steady-state levels, its processing into gp120/gp41, and its mass by inducing glycan removal in a manner dependent on its native signal sequence and the proteasome. Therefore, GPG-NH(2) negatively impacts Env maturation, facilitating its targeting for endoplasmic reticulum-associated protein degradation, where Env is deglycosylated en route to its degradation. These findings illustrate that nontoxic drugs such as GPG-NH(2), which can selectively target glycoproteins to existing cellular degradation pathways, may be useful for pathogen therapy.
Jejcic
Alenka
A
Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Stockholm, SE-141 86, Sweden.
Daniels
Robert
R
Goobar-Larsson
Laura
L
Hebert
Daniel N
DN
Vahlne
Anders
A
D000998:Antiviral Agents / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D015752:Genes, env; D015497:HIV-1 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D011134:Polysaccharides / Q000737:chemistry; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011489:Protein Denaturation; D017434:Protein Structure, Tertiary; D013347:Subcellular Fractions; D019065:Virus Assembly; D014779:Virus Replication
D000998:Antiviral Agents; D011134:Polysaccharides; D046988:Proteasome Endopeptidase Complex