Small Molecule Targets Env for Endoplasmic Reticulum-Associated Protein Degradation and Inhibits Human Immunodeficiency Virus Type 1 Propagation

摘要: 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-NH2), dramatically reduced the infectivity released viral particles by decreasing their Env incorporation. The mechanism GPG-NH2 was uncovered examining expression maturation in treated cells. found affect significantly steady-state levels, processing into gp120/gp41, mass inducing glycan removal manner native signal sequence proteasome. Therefore, negatively impacts maturation, facilitating targeting for endoplasmic reticulum-associated protein degradation, where deglycosylated en route degradation. These findings illustrate nontoxic drugs such as GPG-NH2, which can selectively target glycoproteins existing cellular degradation pathways, may be useful pathogen therapy. reticulum (ER) contains number molecular chaperones folding factors aid proteins traverse secretory pathway. This process strictly monitored ER quality control system, selects properly folded export Golgi (16) targets misfolded destruction through ER-associated pathway (ERAD) (4, 28). Once an selected substrate ERAD, it translocated from lumen cytosol translocon. retrotranslocation thought driven either cytosolic AAA-ATPase p97 (39) or 19S proteasome cap (23).