作者: Zhang, Jiao ; Chang, Qing ; Liu, Gao-Jing ; Liu, Xiu-Yun ; Chen, Qiong-Fang ; Hua, Rong ; Xu, Dong-Ming ; Li, Kai-Qin ; Liu, Zhen ; Xie, Yun-Hua ; Zhao, Bo ; Huang, Xiao-Yan ; Tu, Qiu

端粒是位于染色体末端的核酸-蛋白复合结构，在染色体末端保护和基因组稳定性中发挥重要功能。端粒损伤与细胞衰老和机体衰老均密切相关。作为长寿哺乳动物，蝙蝠表现出独特的端粒调控模式，例如显著上调端粒选择性延长(ALT)通路、DNA修复通路和DNA复制通路众多关联基因的表达水平。然而，具体的上游促进因子仍不清楚。该研究通过跨物种比较解析，确定经典的低氧响应因子EPAS1在蝙蝠端粒保护中发挥重要功能。蝙蝠成纤维细胞持续高表达EPAS1。EPAS1促进端粒蛋白复合体（shelterin）核心组分TRF1和TRF2，以及DNA修复因子RAD50的转录表达，使蝙蝠成纤维细胞在长期连续扩增过程中保持端粒稳定，避免细胞衰老。通过挖掘人类肺脏单细胞转录组图谱，发现EPAS1主要表达于人肺内皮细胞亚群，且在60至70岁人群的肺内皮细胞中的表达量显著降低。利用体外培养的人肺内皮细胞模型和博来霉素诱导的活体小鼠肺损伤模型，证实EPAS1在蝙蝠和人端粒保护中的功能和机制高度保守，发现外源添加EPAS1激动剂M1001能够显著改善博莱霉素诱导的肺端粒损伤和衰老表型。综上所述，该研究聚焦蝙蝠端粒特征，发现了EPAS1在端粒保护中的新功能和新机制，评估了化合物M1001在端粒稳定和抗衰老中的应用价值，强调了从长寿物种蝙蝠中发掘抗衰老新策略的路径可行性。.

2021-02-01·European Journal of Medicinal Chemistry1区 · 医学

Insight into the binding mode of HIF-2 agonists through molecular dynamic simulations and biological validation

1区 · 医学

Article

作者: Yu, Quanwei ; Zhang, Xiaojin ; Yu, Yancheng ; Wu, Chenyang ; Liu, Simeng

Hypoxia-inducible factor-2 (HIF-2), a heterodimeric transcriptional protein consisting of HIF-2α and aryl hydrocarbon receptor nuclear translocator (ARNT) subunits, has a broad transcriptional profile that plays a vital role in human oxygen metabolism. M1001, a HIF-2 agonist identified by high-throughput screening (HTS), is capable of altering the conformation of Tyr281 of the HIF-2α PAS-B domain and enhancing the affinity of HIF-2α and ARNT for transcriptional activation. M1002, an analog of M1001, shows improved efficacy than M1001. However, the cocrystal structure of M1001 and HIF-2 has some defects in revealing the agonist binding mode due to the relatively low resolution, while the binding mode of M1002 remained unexplored. To in-depth understand agonist binding profiles, herein, the molecular dynamic (MD) simulations was applied to construct a stable agonist-protein model, and a possible binding mode was proposed through the analysis of the binding free energy and hydrogen bonding of the simulation results. Nine compounds were then synthesized and evaluated to verify the proposed binding mode. Among them, compound 10 manifested improved agonistic activity and reduced toxicity compared to M1002. This study provides deep insight into the binding mode of such HIF-2 agonists, which would be useful for designing novel agonists for HIF-2.

1995-07-01·Proceedings of the National Science Council, Republic of China. Part B, Life sciences

Production, purification and characterization of two proteinaceous hen-egg-white lysozyme inhibitors from Pseudomonas aeruginosa M-1001.

Article

作者: Pai, C S ; Shieh, S T ; Wang, S L

Two proteinaceous lysozyme inhibitors, hen-egg-white lysozyme inhibitors F-I and F-II, were isolated from the culture broth of a bacterial strain identified as Pseudomonas aeruginosa M-1001. Maximum lysozyme inhibitory activity was obtained when the bacterium was grown aerobically in a medium consisting of 0.25% glucose, 0.25% beef extract, 0.25% polypepton, 1.0% sodium L-glutamate, and 1.0% soluble starch (pH 7.0) at 37 degrees C after 20-24 hrs. F-I and F-II were purified 20 and 7.5-fold, respectively, from the culture supernatant of P. aeruginosa M-1001 by ammonium sulfate fractionation, DEAE-Sepharose CL-6B column chromatography, and Sephacryl S-200 gel chromatography. The molecular weights of F-I and F-II were estimated to be about 57,000 and 33,000, by SDS-PAGE, respectively. F-I was stable in a pH range between 6 and 10 and below 50 degrees C. F-II was stable in a pH range between 6 and 11 and below 40 degrees C. Many Gram-positive bacteria were found to be inhibited by the crude lysozyme inhibitors.

100 项与 M-1001 相关的药物交易

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