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  • br Oxidoreductase like MEM for prodrug activation br Future

    2020-01-23


    Oxidoreductase-like MEM for prodrug activation
    Future outlook Although MEM-mediated prodrug activation has been performed by different MEMs and prodrugs, and their effectiveness have been proved in vivo, only a few types of MEMs or prodrugs have been explored in prodrug activation until now [28], [30], [31], [32], and most of developed MEMs have been widely used for molecular detection [20], [24]. Generally speaking, the csMEMs are more researched in prodrug activation compared with npMEMs and mofMEMs. In particular, the npMEMs have never been used as the convertor for prodrug activation even though many strategies can synthesize different kinds of npMEMs with many advantages superior to natural enzymes, including high stability, low cost, facile functionalization and tunable size. Nevertheless, there are a great potential for MEMs to be effective used in prodrug activation, owing to the similar functions with natural enzymes, maturing preparation methods and other advantages compared with natural enzymes. In order to know well about the prodrug activation mediated by MEMs, the cases of practical and potential prodrug activation are listed in Table 2. Although the perfect examples for practical prodrug activation are relative less, ones for potential prodrug activation are more and inspiring. The potential prodrug activation can be classified into two types. In type I, the true MEMs should be completed by loading the naked catalytic cores into the scaffolds. In type II, many perfect MEMs have been used for catalyzing the model molecules, whose catalytic styles just correspond to some practical prodrug activations by natural enzymes. Therefore, these MEMs are greatly potential for practical activation. In order to improve the effectiveness and usability of the prodrug activation mediated by MEMs, some further studies are interesting and essential. First, the exploration of MEMs and prodrugs need to be mutually dependent. The effective MEMs should be developed according to the existing prodrugs. Meanwhile, smarter prodrugs can be designed based on the multifunctional MEMs. The types of well-known MEMs are much fewer than that of natural enzymes, or the detailed functions of many MEMs have not been fully explored, which limits their application for prodrug activation. Second, it is known that the controllability of EAPT based on natural raloxifene hydrochloride australia is hard to realize, while the MEMs provided a good opportunity for improving the controllability of prodrug therapy. One of the most significant advantages for MEMs is that they can be easily modified by covalent or non-covalent reactions. By modifications, the MEMs can be endowed with the target ability and controlled catalysis ability. A representative example for controlled prodrug activation was the concept of gatekeeper designed by Rotello and his co-workers [28]. Third, designing MEMs from function mimic to structure mimic is important. From metal complexes to csMEMs, the catalytic activity is gradually improved, and other properties including water-solubility, stability and usability are also promoted. On the other hand, the ligands chelating metal ion can also be optimized for increasing the catalytic ability [91]. The bioactive natural enzymes are the result of natural selection for a long time, so their structures are almost optimized. The MEMs based on function mimic can realize basic catalysis, but many other properties including selectivity and fast turnover rate are still weak [64], [135]. The csMEMs and mofMEM with small size and porosity provide an opportunity for further mimicking the natural enzyme both in function and in structure, which is essential for boosting the EAPT. Finally, the toxicity of MEMs need to be considered, although the existed researches don\'t observe the significant toxicity from the MEMs.
    Conclusions
    Introduction Enzymes are extraordinary molecular machines that can increase the rate of chemical reactions in cells by many orders of magnitude. An understanding of the structural dynamics involved in enzymatic catalysis is of great benefit to synthetic biology approaches and rational drug-discovery programs. While most enzymes act specifically by catalyzing a single reaction, some of them are more versatile and promote multiple reactions in response to changing cellular contexts. PPIP5K2, a diphosphoinositol pentakisphosphate kinase (Wang et al., 2012), is one such enzyme. Its biological function is of particular interest for exercising stimulus-dependent spatiotemporal control over the synthesis of inositol pyrophosphates (PP-IPs), small regulatory molecules involved in a large array of signal transduction pathways (Wilson et al., 2013). In particular, PPIP5K2 mediates cellular phosphate homeostasis. Since its kinase activity acts as a sensor of extracellular inorganic phosphate levels (Gu et al., 2017), dysfunctional PPIP5K2 activity in the inner ear results in hair cell loss and deafness (Yousaf et al., 2018).