Journal of Pharmaceutical Analysis
·
2025
·
IF 8.9
Rong Zhu,Pu Wang,Sheng-Lan Qi,Yu Zhang,Chun-Lan Xie,Ya Yang,Cong Hu,Zi-Qiong Zhou,Dong-Fang Zhao,Chao Yang,Jie Sun,Xian-Wen Yang,Guang-Bo Ge,Ping Wang
Human catechol- O -methyltransferase (COMT) is a key target for neuropsychiatric disorders. Inhibiting COMT to prevent levodopa metabolism is a crucial strategy for Parkinson’s disease treatment. While clinically used COMT inhibitors are primarily nitrocatechol-based, they often cause adverse effects, prompting efforts to develop safer non-nitrocatechol alternatives. In this study, baicalein ( BA ) was identified as a potent lead compound for COMT inhibition after screening a series of natural flavonoids using a fluorescence-based visualization inhibitor screening method. Subsequent multi-dimensional structural optimizations addressed the druggable deficiencies of BA , resulting in compound BA24 , which demonstrated a 26-fold increase in cellular COMT inhibition and approximately 10-fold improvements in metabolic stability, membrane permeability and oral bioavailability, respectively, compared to BA . Mechanistically, BA24 competitively inhibited COMT by binding to the catechol pocket with a K i of 89.28 nM. Furthermore, BA24 exhibited favorable safety profiles and significantly modulated levodopa metabolism in rats. Additionally, the relationships between the structural properties, inhibitory activity and metabolic stability of flavonoids as COMT inhibitors were comprehensively investigated. Collectively, this work not only presents a novel non-nitrocatechol COMT inhibitor with favorable safety profiles and potent anti-COMT effects both in vitro and in vivo , but also provides valuable insights into optimizing the druggability of flavonoids as lead compounds.
研究领域:
药理学
·
药物化学
·
神经科学
·
药物发现
·
生物化学
✓ 已验证
DOI
高影响因子
MOLECULAR NUTRITION & FOOD RESEARCH
·
2013
·Vol. 57
·期 5
·877-885
·
IF 4.31
Zhong-Jian Chen,Yan-Qing Dai,Si-Si Kong,Fei-Feng Song,Li-Ping Li,Jian-Feng Ye,Ru-Wei Wang,Su Zeng,Hui Zhou,Hui-Di Jiang
Scope The study aimed to investigate the regioselectivity of methylation of luteolin (3′,4′,5,7-tetrahydroxyflavone) in human in vitro and in vivo. Methods and results Recombinant human catechol- O -methyltransferase (COMT) and human liver S9 were utilized to study the kinetics of meta (3′)- and para (4′)- methylation of luteolin, and urine samples from volunteers after giving a luteolin-containing formulation were collected to determine the ratio of para-/meta-production. The results showed luteolin favored a para-methylation, with a ratio of of para-/meta-production in CL int (1.43 in recombinant human COMT and 1.47 in human liver S9), which was contrary to the known substrates of COMT. However, the result of urine sample assay showed a preference of meta-methylation with a ratio of of para-/meta-production (0.460 ± 0.126). To elucidate the mechanism for different preference of methylation of luteolin in vitro and in vivo, metabolism stability of the meta- and para-methylated luteolin was evaluated in human liver microsomes and recombinant human CYP450s, which revealed that para-methylated luteolin was more easily demethylated by human CYP1A2 and CYP3A4/5 than meta-methylated luteolin. Conclusion Luteolin was a rare substrate of human COMT favoring a para-methylation, but further demethylation by human CYP1A2 and CYP3A4/5 caused a preference of accumulation in meta-methylated luteolin in vivo.
研究领域:
药理学
·
生物化学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2017
·
IF 3.255
Yuan Wang,Qing Li,Yue Dai,Ronghua Pan,Yufeng Xia
A specific and sensitive LC–MS/MS method was established for the simultaneous determination of bergenin, protocatechuic acid and gallic acid, the main active constituents of Saxifraga stolonifera (L.) Meerb. herb, in rat plasma. After fully validated, the method was applied to the comparative pharmacokinetic studies of the three compounds orally administered alone and in combination in the S. stolonifera extract, respectively. The results showed that the pharmacokinetic parameters, including C max , T max , AUC, CL z /F, MRT 0-∞ , were significantly different for both bergenin and protocatechuic acid in the extract as compared to the corresponding compounds administered alone. However, the pharmacokinetic behavior of gallic acid in the extract did not differ from that administered alone. Further studies found that quercetin, coexisting in the herb extract, significantly decreased the glucuronidation of bergenin through inhibiting the activities of UGT1A1 and UGT1A3, and reduced the metabolism of protocatechuic acid by inhibiting the activity of catechol-O-methyltransferase. Quercetin and other flavonoids occurring in the S. stolonifera extract might increase the absorption and improve the bioavailability of bergenin and protocatechuic acid by slowing down the liver metabolism. The findings provide a good guidance for the development and clinical application of S. stolonifera .
研究领域:
药理学
·
分析化学
·
传统医学
✓ 已验证
DOI
PubMed
高影响因子
IUBMB LIFE
·
2018
·Vol. 71
·期 3
·330-339
·
IF 3.236
Qing Wang,Maikun Teng,Xu Li
Catechol- O -methyltransferase (COMT 1 ) catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to various catechol substrates. COMTs play vital roles in physiological processes in animals, plants, and fungi, as well as bacteria, and have essential application values in industry. sp COMT is a probable COMT from Schizosaccharomyces pombe . It has an extraordinary intracellular distribution different from other homologs and would thus be predicted to perform a distinct physiological function. In this report, recombinant sp COMT was purified and kinetically characterized for the first time. The enzymology assays indicate that sp COMT is a metal-dependent enzyme and belongs to class I OMTs. In addition, the crystal structures of apo- sp COMT and SAM-complexed sp COMT were also presented, revealing that sp COMT possesses a conserved SAM-binding site and Mg 2+ pocket, but a distinct substrate pocket was not present in homologs. The mutagenesis ITC analysis revealed the SAM recognition characteristics of sp COMT. Based on all of the above findings, we speculated about the putative substrates’ characteristics and the substrate recognition mechanisms of sp COMT. This work will help in elucidating the physiological functions of sp COMT in S. pombe . © 2018 IUBMB Life, 71(3):330–339, 2019
研究领域:
生物化学
·
分子生物学
·
结构生物学
✓ 已验证
DOI
PubMed
高影响因子
Microbial Cell Factories
·
2021
·Vol. 20
·期 1
·1-13
·
IF 5.328
Zhang Yanfeng,He Yongzhi,Zhang Nan,Gan JiaJia,Zhang Shan,Dong Zhiyang
Background Melatonin has attracted substantial attention because of its excellent prospects for both medical applications and crop improvement. The microbial production of melatonin is a safer and more promising alternative to chemical synthesis approaches. Researchers have failed to produce high yields of melatonin in common heterologous hosts due to either the insolubility or low enzyme activity of proteins encoded by gene clusters related to melatonin biosynthesis. Results Here, a combinatorial gene pathway for melatonin production was successfully established in Escherichia coli by combining the physostigmine biosynthetic genes from Streptomyces albulus and gene encoding phenylalanine 4-hydroxylase (P4H) from Xanthomonas campestris and caffeic acid 3- O -methyltransferase (COMT) from Oryza sativa . A threefold improvement of melatonin production was achieved by balancing the expression of heterologous proteins and adding 3% glycerol. Further protein engineering and metabolic engineering were conducted to improve the conversion of N -acetylserotonin (NAS) to melatonin. Construction of COMT variant containing C303F and V321T mutations increased the production of melatonin by fivefold. Moreover, the deletion of speD gene increased the supply of S-adenosylmethionine (SAM), an indispensable cofactor of COMT, which doubled the yield of melatonin. In the final engineered strain EcMEL8, the production of NAS and melatonin reached 879.38 ± 71.42 mg/L and 136.17 ± 1.33 mg/L in a shake flask. Finally, in a 2-L bioreactor, EcMEL8 produced 1.06 ± 0.07 g/L NAS and 0.65 ± 0.11 g/L melatonin with tryptophan supplementation. Conclusions This study established a novel combinatorial pathway for melatonin biosynthesis in E. coli and provided alternative strategies for improvement of melatonin production.
研究领域:
生物技术
·
微生物学
·
生物化学
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2023
·Vol. 12
·期 12
·2202424
·
IF 10
Dongdong Guo,Xiaoyong Dai,Kewei Liu,Yuhong Liu,Jiamin Wu,Kun Wang,Shengwei Jiang,Fen Sun,Lijun Wang,Bing Guo,Dongye Yang,Laiqiang Huang
While calcium-overload-mediated therapy (COMT) is a promising but largely untapped therapeutic strategy, combinatory therapy greatly boosts treatment outcomes with integrated merits of different therapies. Herein, a BPQD@CaO 2 -PEG-GPC3Ab nanoplatform is formulated by integrating calcium peroxide (CaO 2 ) and black phosphorus quantum dot (BPQD, photosensitizer) with active-targeting glypican-3 antibody (GPC3Ab), for combinatory photodynamic therapy (PDT) and COMT in response to acidic pH and near-infrared (NIR) light, wherein CaO 2 serves as the reservoir of calcium ions (Ca 2+ ) and hydrogen peroxide (H 2 O 2 ). Navigated by GPC3Ab to tumor cells at acidic pH, the nanoparticle disassembles to CaO 2 and BPQD; CaO 2 produces COMT Ca 2+ and H 2 O 2 , while H 2 O 2 makes oxygen (O 2 ) to promote PDT; under NIR irradiation BPQD facilitates not only the conversion of O 2 to singlet oxygen ( 1 O 2 ) for PDT, but also moderate hyperthermia to accelerate NP dissociation to CaO 2 and BPQD, and conversions of CaO 2 to Ca 2+ and H 2 O 2 , and H 2 O 2 to O 2 , to enhance both COMT and PDT. After supplementary ionomycin treatment to induce intracellular Ca 2+ bursts, the multimodal therapeutics strikingly induce hepatocellular carcinoma apoptosis, likely through the activation of the calpains and caspases 12, 9, and 3, up-regulation of Bax and down-regulation of Bcl-2 proteins. This nanoplatform enables a mutually-amplifying and self-reinforcing synergistic therapy.
研究领域:
癌症治疗
·
纳米技术
·
光动力疗法
·
钙信号
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）