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

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 <i>in vitro</i>. Importantly, in contrast to estriol and other steroids, SG13-136 lacked estrogenic activity, showing no overt toxicity <i>in vivo</i>. 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.