Kaplan, Anna; Gaschler, Michael M.; Dunn, Denise E.; Colligan, Ryan; Brown, Lewis M.; Palmer, Arthur G. III; Lo, Donald C.; Stockwell, Brent R. published the artcile< Small molecule-induced oxidation of protein disulfide isomerase is neuroprotective>, Synthetic Route of 21725-69-9, the main research area is protein disulfide isomerase oxidation neuroprotective pharmacokinetics; drug; inhibitor; neuroprotection; protein disulfide isomerase; small molecule.
Protein disulfide isomerase (PDI) is a chaperone protein in the endoplasmic reticulum that is up-regulated in mouse models of, and brains of patients with, neurodegenerative diseases involving protein misfolding. PDI’s role in these diseases, however, is not fully understood. Here, the authors report the discovery of a reversible, neuroprotective lead optimized compound I, that acts as a modulator of PDI. I was identified using a high-throughput screen of ∼10,000 lead-optimized compounds for potent rescue of viability of PC12 cells expressing mutant huntingtin protein, followed by an evaluation of compounds on PDI reductase activity in an in vitro screen. Isothermal titration calorimetry and fluorescence experiments revealed that binding to PDI was reversible with a Kd of 62 nM, suggesting I to be the most potent PDI inhibitor reported to date. Using 2D heteronuclear single quantum correlation NMR experiments, the authors were able to map the binding site of I as being adjacent to the active site and to observe that binding of I forces PDI to adopt an oxidized conformation. Furthermore, the authors found that I-induced oxidation of PDI has a neuroprotective effect not only in cell culture, but also in corticostriatal brain slice cultures. I exhibited high stability in mouse liver microsomes and blood plasma, low intrinsic microsome clearance, and low plasma-protein binding. These results suggest that I is a promising lead compound to evaluate the potential therapeutic effects of modulating PDI in animal models of disease.
Proceedings of the National Academy of Sciences of the United States of America published new progress about Homo sapiens. 21725-69-9 belongs to class isoxazole, and the molecular formula is C7H5NO2, Synthetic Route of 21725-69-9.
Referemce:
Isoxazole – Wikipedia,
Isoxazole | C3H3NO – PubChem