Capture and Identification of Dual Specificity Mitogen-Activated Protein Kinase Kinase 7 as a Direct Proteomic Target of Berberine to Affect the c-JunN-Terminal Kinase Pathway

Zeng, Qingpeng; Wei, Wei; Fan, Tianyun; Deng, Hongkui; Guo, Xixi; Zhao, Liping; Zhang, Xintong; Tang, Sheng; Jiang, Jian‐Dong; Li, Yinghong; Wang, Yanxiang; Song, Dan–Qing

doi:10.31635/ccschem.021.202100986

Cited by 6 publications

(3 citation statements)

References 36 publications

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“…ABPP technique, a chemical biological tool for target protein exploration, 43 – 45 was applied for the target fishing and identifying of 8 in this study, and the workflow of the specific process was described in Supplementary Fig. S5 .…”

Section: Resultsmentioning

confidence: 99%

A deep learning-driven discovery of berberine derivatives as novel antibacterial against multidrug-resistant Helicobacter pylori

Guo,

Zhao,

et al. 2024

Sig Transduct Target Ther

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Helicobacter pylori (H. pylori) is currently recognized as the primary carcinogenic pathogen associated with gastric tumorigenesis, and its high prevalence and resistance make it difficult to tackle. A graph neural network-based deep learning model, employing different training sets of 13,638 molecules for pre-training and fine-tuning, was aided in predicting and exploring novel molecules against H. pylori. A positively predicted novel berberine derivative 8 with 3,13-disubstituted alkene exhibited a potency against all tested drug-susceptible and resistant H. pylori strains with minimum inhibitory concentrations (MICs) of 0.25–0.5 μg/mL. Pharmacokinetic studies demonstrated an ideal gastric retention of 8, with the stomach concentration significantly higher than its MIC at 24 h post dose. Oral administration of 8 and omeprazole (OPZ) showed a comparable gastric bacterial reduction (2.2-log reduction) to the triple-therapy, namely OPZ + amoxicillin (AMX) + clarithromycin (CLA) without obvious disturbance on the intestinal flora. A combination of OPZ, AMX, CLA, and 8 could further decrease the bacteria load (2.8-log reduction). More importantly, the mono-therapy of 8 exhibited comparable eradication to both triple-therapy (OPZ + AMX + CLA) and quadruple-therapy (OPZ + AMX + CLA + bismuth citrate) groups. SecA and BamD, playing a major role in outer membrane protein (OMP) transport and assembling, were identified and verified as the direct targets of 8 by employing the chemoproteomics technique. In summary, by targeting the relatively conserved OMPs transport and assembling system, 8 has the potential to be developed as a novel anti-H. pylori candidate, especially for the eradication of drug-resistant strains.

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Section: Resultsmentioning

confidence: 99%

A deep learning-driven discovery of berberine derivatives as novel antibacterial against multidrug-resistant Helicobacter pylori

Guo,

Zhao,

et al. 2024

Sig Transduct Target Ther

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“…Recently, we captured multiple target proteins of BBR’s anti-inflammatory effects using the activity-based protein profiling technology, , and a weak interaction was identified between 2v and vasodilator-stimulated phosphoprotein (VASP), whose phosphorylation is closely associated with its downstream antiplatelet aggregation effects. − Then, VASP phosphorylation of compound 2v was conducted, and as described in Figure D–G, it enhanced in a concentration-dependent manner, a comparable activity to that of BBR.…”

Section: Results and Discussionmentioning

confidence: 99%

Palmatine Derivatives as Potential Antiplatelet Aggregation Agents via Protein Kinase G/Vasodilator-Stimulated Phosphoprotein and Phosphatidylinositol 3-Kinase/Akt Phosphorylation

et al. 2022

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Sixty palmatine (PMT) derivatives were synthesized and evaluated for antiplatelet aggregation taking berberine as the lead, and the structure−activity relationship was first systematically described. Among them, compound 2v showed the best potency in reducing adenosine diphosphate (ADP)-induced platelet aggregation in a dose-dependent manner. It greatly suppressed ADP-induced platelet aggregation, activation, and Akt phosphorylation in vitro and ex vivo after oral administration to mice. It also effectively inhibited carrageenan-induced thrombus formation in the mouse tail and lung, as well as reduced the serum P-selectin level. Compound 2v might simultaneously bind to protein kinase G to improve vasodilator-stimulated phosphoprotein phosphorylation and bind to phosphatidylinositol 3-kinase to inhibit Akt phosphorylation, which synergically reduced platelet aggregation, thereby achieving antithrombotic efficacy. Therefore, PMT derivatives constituted a novel family of antiplatelet aggregation agents with the advantage of a good safety profile, worthy of further investigation.

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“…The known direct targets of BBR include RXRα (retinoid X receptor α) [ 19 ], G4s (G quadruplexes) [ 30 ], UHRF1 (ubiquitin-like with PHD and RING finger domains) [ 31 ], and MAP2K7 (mitogen-activated protein kinase 7) [ 32 ] in human somatic cells, as well as FtsZ (filamentation temperature sensitive protein Z) in microorganisms [ 33 ]. BBR interacts with them to exert antitumor, anti-inflammatory, and antibacterial effects, respectively.…”

Section: Discussionmentioning

confidence: 99%

Identification of FtfL as a novel target of berberine in intestinal bacteria

Yan,

Fang,

Yang

et al. 2023

BMC Biol

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Background Berberine (BBR) is a commonly used anti-intestinal inflammation drug, and its anti-cancer activity has been found recently. BBR can intervene and control malignant colorectal cancer (CRC) through intestinal microbes, but the direct molecular target and related mechanism are unclear. This study aimed to identify the target of BBR and dissect related mechanisms against the occurrence and development of CRC from the perspective of intestinal microorganisms. Results Here, we found that BBR inhibits the growth of several CRC-driving bacteria, especially Peptostreptococcus anaerobius. By using a biotin-conjugated BBR derivative, we identified the protein FtfL (formate tetrahydrofolate ligase), a key enzyme in C1 metabolism, is the molecular target of BBR in P. anaerobius. BBR exhibits strong binding affinity and potent inhibition on FtfL. Based on this, we determined the crystal structure of PaFtfL (P. anaerobius FtfL)-BBR complex and found that BBR can not only interfere with the conformational flexibility of PaFtfL tetramer by wedging the tetramer interface but also compete with its substrate ATP for binding within the active center. In addition, the enzymatic activities of FtfL homologous proteins in human tumor cells can also be inhibited by BBR. Conclusions In summary, our study has identified FtfL as a direct target of BBR and uncovered molecular mechanisms involved in the anti-CRC of BBR. BBR interferes with intestinal pathogenic bacteria by targeting FtfLs, suggesting a new means for controlling the occurrence and development of CRC.

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Capture and Identification of Dual Specificity Mitogen-Activated Protein Kinase Kinase 7 as a Direct Proteomic Target of Berberine to Affect the c-JunN-Terminal Kinase Pathway

Cited by 6 publications

References 36 publications

A deep learning-driven discovery of berberine derivatives as novel antibacterial against multidrug-resistant Helicobacter pylori

A deep learning-driven discovery of berberine derivatives as novel antibacterial against multidrug-resistant Helicobacter pylori

Palmatine Derivatives as Potential Antiplatelet Aggregation Agents via Protein Kinase G/Vasodilator-Stimulated Phosphoprotein and Phosphatidylinositol 3-Kinase/Akt Phosphorylation

Identification of FtfL as a novel target of berberine in intestinal bacteria

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