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| Type |
Poster Presentation |
| Area |
Medicinal Chemistry |
| Room No. |
Event Hall |
| Time |
4월 19일 (목요일) 11:00~12:30 |
| Code |
MEDI.P-607 |
| Subject |
Discovery of Protein-protein Interaction Inhibitor as Nrf2 Activator for Parkinson's Disease Therapy |
| Authors |
Siwon Kim, Ki Duk Park*
Convergence Research Center for DTC, Korea Institute of Science and Technology, Korea
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| Abstract |
Persistent oxidative stress and chronic inflammation have been implicated in Parkinson’s diseases (PD). Keap1-Nrf2 system is considered as an attractive strategy against oxidative stress. Since Keap1 is cysteine-rich, Nrf2 activators such as dimethyl fumarate (DMF), which targets the cysteine residues of Keap1, has been developed. However, this approach is less specific to Keap1 and can cause side effect by reacting with other cysteines of proteins. In this study, we searched for compounds using the virtual screening approach and found a hit compound KKPA4026 as a direct inhibitor of the Keap1-Nrf2 protein-protein interaction (PPI). First, we found that KKPA4026 effectively activate Nrf2 nuclear translocation through the cell-based Keap1-Nrf2 assay (EC50 of 1.46 μM). KKPA4026 was confirmed to activate Nrf2 and induce expression of antioxidant enzymes in BV-2 microglial cells. In additions, KKPA4026 showed anti-inflammatory effects by reducing nitrite and pro-inflammatory cytokines in lipopolysaccharide (LPS)-stimulated BV-2 cells. In the MPTP-induced mouse model of PD, orally administered KKPA4026 attenuated PD-associated motor impairment and resulted in the protection of the dopaminergic (DAergic) neurons. These results indicate that KKPA4026, a small molecular PPI inhibitor of Keap1-Nrf2, has neuroprotective effects and can be a potential candidate for PD therapy. |
| E-mail |
H15512@kist.re.kr |
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121st General Meeting of the KCS