1.Discovery and identification of EIF2AK2 as a direct key target of berberine for anti-inflammatory effects.
Wei WEI ; Qingxuan ZENG ; Yan WANG ; Xixi GUO ; Tianyun FAN ; Yinghong LI ; Hongbin DENG ; Liping ZHAO ; Xintong ZHANG ; Yonghua LIU ; Yulong SHI ; Jingyang ZHU ; Xican MA ; Yanxiang WANG ; Jiandong JIANG ; Danqing SONG
Acta Pharmaceutica Sinica B 2023;13(5):2138-2151
Using chemoproteomic techniques, we first identified EIF2AK2, eEF1A1, PRDX3 and VPS4B as direct targets of berberine (BBR) for its synergistically anti-inflammatory effects. Of them, BBR has the strongest affinity with EIF2AK2 via two ionic bonds, and regulates several key inflammatory pathways through EIF2AK2, indicating the dominant role of EIF2AK2. Also, BBR could subtly inhibit the dimerization of EIF2AK2, rather than its enzyme activity, to selectively modulate its downstream pathways including JNK, NF-κB, AKT and NLRP3, with an advantage of good safety profile. In EIF2AK2 gene knockdown mice, the inhibitory IL-1β, IL-6, IL-18 and TNF-α secretion of BBR was obviously attenuated, confirming an EIF2AK2-dependent anti-inflammatory efficacy. The results highlight the BBR's network mechanism on anti-inflammatory effects in which EIF2AK2 is a key target, and inhibition of EIF2AK2 dimerization has a potential to be a therapeutic strategy against inflammation-related disorders.
2.Evolution and development of potent monobactam sulfonate candidate IMBZ18g as a dual inhibitor against MDR Gram-negative bacteria producing ESBLs.
Zhiwen LI ; Zhihao GUO ; Xi LU ; Xican MA ; Xiukun WANG ; Rui ZHANG ; Xinxin HU ; Yanxiang WANG ; Jing PANG ; Tianyun FAN ; Yonghua LIU ; Sheng TANG ; Haigen FU ; Jingpu ZHANG ; Yinghong LI ; Xuefu YOU ; Danqing SONG
Acta Pharmaceutica Sinica B 2023;13(7):3067-3079
A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria. Compound 33a (IMBZ18G) is highly effective in vitro and in vivo against clinically intractable multi-drug-resistant (MDR) Gram-negative strains, with a highly druglike nature. The checkerboard assay reveals its significant synergistic effect with β-lactamase inhibitor avibactam, and the MIC values against MDR enterobacteria were reduced up to 4-512 folds. X-ray co-crystal and chemoproteomic assays indicate that the anti-MDR bacteria effect of 33a results from the dual inhibition of the common PBP3 and some class A and C β-lactamases. Accordingly, preclinical studies of 33a alone and 33a‒avibactam combination as potential innovative candidates are actively going on, in the treatment of β-lactamase-producing MDR Gram-negative bacterial infections.