Dual inhibition of aminoacyl-tRNA synthetase interacting multifunctional protein-2 and α-synuclein by steroid derivative is neuroprotective in Parkinson's model

Jeong-Yong Shin; Min Woo Ha; Ji Hun Kim; Jiwon Cheon; Gum Hwa Lee; Seung-Mann Paek; Yunjong Lee

doi:10.1016/j.isci.2024.111165

Dual inhibition of aminoacyl-tRNA synthetase interacting multifunctional protein-2 and α-synuclein by steroid derivative is neuroprotective in Parkinson's model

iScience. 2024 Oct 11;27(11):111165. doi: 10.1016/j.isci.2024.111165. eCollection 2024 Nov 15.

Authors

Jeong-Yong Shin¹, Min Woo Ha², Ji Hun Kim¹, Jiwon Cheon¹, Gum Hwa Lee³, Seung-Mann Paek⁴, Yunjong Lee¹

Affiliations

¹ Department of Pharmacology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, Republic of Korea.
² Jeju Research Institute of Pharmaceutical Sciences, College of Pharmacy, Jeju National University, 102 Jejudaehak-ro, Jeju 63243 Jeju-do, Republic of Korea.
³ College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea.
⁴ College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju-daero, Jinju 52828, Gyeongnam-do, Republic of Korea.

Abstract

Aminoacyl-tRNA synthetase interacting multifunctional protein-2 (AIMP2), a parkin substrate, possesses self-aggregating properties, potentiating α-synuclein aggregation and neurotoxicity in PD. Thus, targeting both α-synuclein and AIMP2 would present an effective treatment for PD pathologies. Herein, we developed small compounds with dual inhibitory activity against AIMP2 and α-synuclein. Structure-activity relationship (SAR) analysis on commercial and newly synthesized steroid derivatives revealed critical chemical moieties for biological AIMP2 and α-synuclein inhibitory function. Among others, the new compound SG13-136 exhibited strong binding affinity and inhibitory function for both AIMP2 and α-synuclein in vitro. Importantly, in contrast to estriol and other steroids, SG13-136 lacked estrogenic activity, showing no overt toxicity in vivo. Furthermore, SG13-136 demonstrated therapeutic protective effects against PD pathologies in cellular and mouse models of α-synucleinopathy. Our study confirms the strategic validity of targeting both AIMP2 and α-synuclein in PD treatment and offers SAR information that could be used for PD drug discovery.

Keywords: biochemistry; molecular biology; neuroscience.