The potential of protein disulfide isomerase as a therapeutic drug target.
Protein disulfide isomerase (PDI) is a multifunctional protein of the thioredoxin superfamily. PDI mediates proper protein folding by oxidation or isomerization and disrupts disulfide bonds by reduction; it also has chaperone and antichaperone activities. Although PDI localizes primarily to the endoplasmic reticulum (ER), it is secreted and expressed on the cell surface. In the ER, PDI is primarily involved in protein folding, whereas on the cell surface, it reduces disulfide bonds. The functions of PDI depend on its localization and the redox state of its active site cysteines. The ER-based functions of PDI are linked to cancer invasion and migration. Surface-associated PDI facilitates the entry of viruses, such as HIV-1, and toxins, such as diphtheria and cholera. Thus, based on its involvement in pathological events, PDI is considered a potential drug target. However, a significant challenge in the therapeutic targeting of PDI is discovering function-specific inhibitors for it. To this end, a wide range of therapeutic agents, such as antibiotics, thiol blockers, estrogenic compounds, and arsenical compounds, have been used, although few are bona fide specific inhibitors. In this review, we will describe the potential of PDI as a therapeutic drug target.
Chemical Biology Core Facility, Chemical Biology Department, RIKEN Advanced Science Institute, Saitama, Japan.
Maola M G
MM
Khan
Siro
S
Simizu
Makoto
M
Kawatani
Hiroyuki
H
Osada
D000818:Animals; D001414:Bacitracin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology; D006801:Humans; D010226:Parabens / Q000494:pharmacology; D019704:Protein Disulfide-Isomerases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D017434:Protein Structure, Tertiary; D012271:Ribostamycin / Q000494:pharmacology; D012717:Sesquiterpenes / Q000494:pharmacology
D004791:Enzyme Inhibitors; D004967:Estrogens; D010226:Parabens; D012717:Sesquiterpenes; C561768:juniferdin; D001414:Bacitracin; D012271:Ribostamycin; D019704:Protein Disulfide-Isomerases