Screening of enzyme inhibitors from traditional Chinese medicine

Traditional Chinese medicine (TCM) has been used for more than 4000 years. By comparison with large combinatorial chemistry libraries and natural products of the West for high-throughput screening (HTS) of new drugs discovery, an advantage of TCM is that the preparation has clear efficacies on the therapy of some diseases. Although the effective components are not clear, the clear efficacies of TCM have been identified for long time practice, Therefore, TCMs should be valuable lead compound libraries with a definite therapy efficacy from the viewpoint of HTS. Nevertheless, current HTS technologies are not easily adapted to investigate TCMs because they are designed for screening a relatively pure known chemical at a known concentration. In contrast, TCMs are mixtures of unknown compounds in unknown concentrations that may differ markedly between samples from different plants. This article reviews the current and future researches on the enzyme inhibitors screening from TCM.     

Tumor-agnostic inhibitors in oncology: A new phase for precision medicine

The study of precision medicine is flourishing in recent decades. Tumor-agnostic therapy is one of the targeted therapies, which can treat the malignant cells regardless of where they grow. Herein we reviewed currently the U.S. FDA-approved tumor-agnostic therapies: one monoclonal antibody as a PD-1 inhibitor called pembrolizumab and four small-molecule kinase inhibitors, larotrectinib, entrectinib, selpercatinib, and pralsetinib. We also summarized the reported synthetic routes toward three drugs and some developing candidates under clinical trials as tumor-agnostic therapy.     

毛细管电泳法研究中草药有效成分对二氢叶酸还原酶的抑制作用

利用已建立的二氢叶酸还原酶抑制剂的毛细管电泳法筛选模型,研究了10种中草药有效成分对二氢叶酸还原酶的抑制作用.经实验测定发现木樨草素、表儿荼素、紫杉醇和槲皮素对二氢叶酸还原酶(DHFR)有抑制作用,且抑制效果为木樨草素>紫杉醇>表儿荼素>槲皮素.通过对产物NADP(氧化型辅酶Ⅱ)峰面积的定量测定,计算了4种抑制剂的抑制率.     

Enzyme inhibitors as chemical tools to study enzyme catalysis: rational design, synthesis, and applications

Carefully designed molecules that are intimately related to the reaction mechanism of enzymes are often highly selective and potent inhibitors that serve as extremely useful chemical probes for understanding the reaction mechanism and structure of enzymes. This article describes the design, synthesis, and applications of specific inhibitors of two mechanistically distinct groups of enzymes, ATP-dependent amide ligases and Ser- and Thr-hydrolases. Our strategy is based on the premise that stable analogues of the transition state (transition-state analogues) are highly potent inhibitors that serve as good mechanistic probes, and that a key structure of a good inhibitor of one enzyme is also utilized for the inhibitors of other enzymes that share the same chemistry in their catalyzed reactions, irrespective of the degree of structural similarity and evolutionary link between the enzymes. According to these principles, we designed and synthesized a series of phosphinate- and sulfoximine-based transition-state analogue inhibitors of glutathione synthetase, gamma-glutamylcysteine synthetase and asparagine synthetase. For the second group of enzymes, we synthesized a gamma-monofluorophosphono glutamate analogue for mechanism-based affinity labeling of gamma-glutamyltranspeptidase and fluorescent phosphonic acid esters for the active-site titration of lipase. These inhibitors were used successfully as ligands for detailed kinetic analyses, X-ray crystallography, and mass analysis of the enzymes to identify the key amino acid residues responsible for catalysis and substrate recognition in the transition state.     

丝素膜固定化丝网印刷酶电极

采用丝网印刷技术制作的一次性薄层碳电极具有良好的分析性能。经化学修饰二茂铁后,以丝素为固定化载体固定含有多酚氧化酶的蘑菇萃取蛋白,所得酸电极对其底物邻苯二酚和多巴胺有良好响应,线性范围为２．０×１０－８～２．０×１０－２,ｍｏｌ／Ｌ,在３０ｓ内即可达到９５％稳态电流。该电极的ＲＳＤ为２．７％,且可保持１０天以上的工作寿命。该酶电极在低温湿润环境中可保存较长时间,因此有较好的商品化前景。     

Enzyme mimics

Chemists are trying to create synthetic molecules which mimic the recognition and catalytic properties of real enzymes. One target of interest is catalysis of reactions for which there are no known natural enzymes. Inspired by the examples of nature, approaches to the design of enzyme mimics for catalysis of Diels-Alder reaction are described. The design is based on porphyrin molecular boxes and zinc co-ordination. The potential of design of enzyme mimics employing cholic acid and other systems is also discussed.     

Enzyme engineering

Enzyme research and development efforts have been shaped by the tools and concepts available for enzyme production and utilization. A new phase of enzymology characterized by the production of modified protein catalysts has begun, made possible by recombinant DNA technology.     

Natural products derived from traditional chinese medicine as novel inhibitors of the epidermal growth factor receptor

The epidermal growth factor receptor (EGFR) has become an important molecular target in cancer therapy. Various small molecules and therapeutic antibodies targeting EGFR family members have been developed during recent years and are established in clinical oncology. However, increasing clinical application of EGFR tyrosine kinase inhibitors has resulted in the development of resistance to EGFR-targeting drugs due to the selection of EGFR-mutated variants. This phenomenon forced the search for novel EGFR inhibitors with activity towards EGFR-mutant tumors. This review describes recent achievements in natural products derived from medicinal plants as novel EGFR inhibitors.     

Chemical Oscillations in Enzyme Kinetics

The Higgins model is a two variable model in enzyme kinetics. In contrast with other popular simple dynamical models like the Lotka-Volterra model, the Higgins model shows steady states, damped oscillations and stable limit cycles. For these three dynamical behaviors, stability analysis yields expressions of the eigenvalues, which are easy to obtain either analytically or with the use of Mathematica. With these expressions we can find the boundaries between the three dynamical regions in parameter space and the bifurcation point. Also, we have compared the Higgins model with the other two variable models and find that the origin of the richer dynamical behavior of the Higgins model is due to the enzymatic step in the mechanism.     

交联酶聚体技术研究进展

交联酶聚体（CLEAs）是一类新型的固定化酶技术,具有制备简单、酶活回收率高、操作和保存稳定性强等优点。近年来,CLEAs技术与材料学、印迹工程、介质工程、反应工程学等相结合取得了一系列新进展,包括载体固定化CLEAs、包埋CLEAs、印迹法CLEAs、多酶CLEAs、CLEAs膜浆反应器等,在手性分子拆分与合成。抗生素生产等领域取得了一些成果。本文对CLEAs酶活影响因素及CLEAs技术的最新研究进展进行了分析与总结,并展望了需进一步深入开展的内容,有助于生物工程、酶工程、化学工程和材料科学等领域相关研究工作的开展。