Chao Yang,Haojie Cai,Xinying Zhu,Lei Zhang,Jing Li
Xanthine oxidoreductase (XOR) and uric acid transporter 1 (URAT1) are two most widely studied targets involved in production and reabsorption of uric acid, respectively. Marketed drugs almost target XOR or URAT1, but sometimes, single agents might not achieve aim of lowering uric acid to ideal value in clinic. Thus, therapeutic strategies of combining XOR inhibitors with uricosuric drugs were proposed and implemented. Based on our initial work of virtual screening, A and B were potential hits for dual-targeted inhibitors on XOR/URAT1. By docking A / B with XOR/URAT1 respectively, compounds I1-7 were designed to get different degree of inhibition effect on XOR and URAT1, and I7 showed the best inhibitory effect on XOR (IC 50 = 0.037 ± 0.001 μM) and URAT1 (IC 50 = 546.70 ± 32.60 μM). Further docking research on I7 with XOR/URAT1 led to the design of compounds II with the significantly improved inhibitory activity on XOR and URAT1, such as II11 and II15 . Especially, for II15 , the IC 50 of XOR is 0.006 ± 0.000 μM, superior to that of febuxostat (IC 50 = 0.008 ± 0.000 μM), IC 50 of URAT1 is 12.90 ± 2.30 μM, superior to that of benzbromarone (IC 50 = 27.04 ± 2.55 μM). In acute hyperuricemia mouse model, II15 showed significant uric acid lowering effect. The results suggest that II15 had good inhibitory effect on XOR/URAT1, with the possibility for further investigation in in-vivo models of hyperuricemia.
Based on analyses of the interaction between febuxostat and xanthine oxidoreductase (XOR), tetrazole was used to replace the carboxyl-thiazole fragment of febuxostat using a bioelectronic isosteric strategy. Three series of compounds were designed. The inhibitory activity against XOR of all compounds was evaluated and their structure–activity relationships determined. The inhibitory activity against XOR of compounds I was weak, with a half-maximal inhibitory concentration (IC 50 ) value > 10 μmol, whereas the inhibitory activity of compounds II and III was increased significantly, among which compounds IIIa (IC 50 = 26.3 ± 1.21 nM) and IIIc (IC 50 = 29.3 ± 0.88 nM) were the best. Molecular docking showed that tetrazole could enter the active cavity instead of a carboxyl group and retain most of the interaction between febuxostat and XOR. For compounds III , the hydrogen bonds with Asn768 and Thr1010 of XOR were absent, but some new interactions were introduced to improve potency. A potassium oxazinate/hypoxanthine-induced model of acute hyperuricemia in mice also showed a significant hypouricemia effect of compounds IIIa , IIIc , and IIIe ( P < 0.01), which was consistent with the results of inhibition in vitro . In conclusion, we identified a promising XOR inhibitor and provided new ideas for the design of XOR inhibitors.
Background High reactive oxygen species (ROS) concentration displays dual functions, potentially promoting both tumor cell death and driving tumor-associated macrophage (TAM) polarization towards the M1-type to elicit a series of antitumor immune responses, positioning ROS as ideal tumor therapeutic molecules. However, sustained efficacy and precise ROS targeting at tumor sites retains numerous challenges. In this study, we present the synthesis of a nanoplatform, ZIF-8@XOR, comprising Xanthine oxidoreductase (XOR) with high intracellular enzymatic activity for high-level ROS generation and ZIF-8, a versatile zeolite imidazolate framework-8 carrier with high tumor site loading and targeting efficiency. Results: Our results revealed that ZIF-8@XOR targets tumor cells and elicits intracellular ROS both in vitro and in vivo, inducing tumor cell death. Moreover, intracellular ROS elicitation in TAM supports macrophage polarization towards the M1-type. In vivo, tumor-associated antigen pool generation from ROS-induced apoptosis of tumor cells further stimulates increased infiltration and macrophage activation in the tumor microenvironment. This, in turn, leads to increased tumor infiltration of CD8 + T cells with a cytokine profile, indicating cytotoxic effects and suggesting a successfully induced adaptive anti-tumor response. Conclusion: The hereby-presented newly developed nanomaterial could serve as a promising novel tool for gastric cancer immunotherapy. Graphical
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