Quinone reductase 2 (QR2) is an enzyme which recognizes putative metabolites of NADH, such as N-methyl- and N-ribosyl-dihydronicotinamide. It has been particularly associated with reactive oxygen species and memory, strongly suggesting a link among QR2 (as a possible key element in pro-oxidation), autophagy, and neurodegeneration[1]. S29434 is a potent, nanomolar inhibitor of QR2 with IC50 of 5-16 nM at different organizational levels[1]. Paraquat (PQ) (30 mg/kg) and S29434 were administered i.p. to Wistar rats and animals were monitored for 28 days. S29434 potently antagonized non-apoptotic PQ-induced cell death, reactive oxygen species (ROS) generation and inhibited cellular QR2 activity. Significantly, S29434 (4.5 mg/kg) potently antagonized PQ-induced systemic toxicity and animal mortality. Microinfusion of S29434 into substantia nigra (SN) prevented severe behavioural and electrocortical effects of PQ which correlated with inhibition of malondialdehyde accumulation in cells and tissues[2].
作用机制
S29434 fits deeply into a QR2 hydrophobic cavity (Protein Data Bank: 3OX3), interacting with subunits A and B with its amido-furan side chains pointing toward the solvent.
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