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Melanotropin Receptors and Signal Transduction
Published in Mac E. Hadley, The Melanotropic Peptides, 2018
Tomi K. Sawyer, Mac E. Hadley, Victor J. Hruby
Signal transduction of the MSH-receptor complex to adenylate cyclase has been supported by several experimental data: α-MSH stimulates intracellular cAMP production in frog (R. pipiens) melanocytes in vitro.34Iontophoretically injected cAMP into single frog (R. pipiens) melanocytes effects melanosome dispersion.25α-MSH stimulates cAMP production in both murine35,36 and human37 melanoma cells and stimulates adenylate cyclase activity dose-dependently in murine melanoma cell-free systems.23,38,39cAMP and N6,O2’-dibutyryl cAMP mimic (presumably, after directly entering the cell) MSH-stimulated melanosome disperison in vitro on both frog and lizard skin melanocytes.40-42Methylxanthines, which are inhibitors of cAMP phosphodiesterase (an intracellular cyclic nucleotide-degrading enzyme) mimic both MSH-stimulated melanosome dispersion on lizard (A. carolinensis) melanocytes43 and MSH-stimulated tyrosinase activity in murine (Cloudman S-91) melanoma cells44.
Shortcomings and Alternatives
Published in Willi Kullmann, Enzymatic Peptide Synthesis, 1987
If nature cannot supply the peptide synthetic chemist with an adequate set of proteases one might proceed according to the motto: “Need a catalyst? Design an enzyme”.17 A variety of proteinaceous and nonproteinaceous compounds have been prepared in an effort to mimic the catalytic action of proteases. (The following references only give a limited survey of this challenging field of enzyme chemistry, 18 to 27.) However, the studies to date on protease mimetics have focused predominantly on their hydrolytic activities, while few reports on enzyme models displaying proteosynthetic capacities have been published. In this respect, the work of Sasaki et al.28 on the preparation of an artificial catalyst for the synthesis of peptide bonds represents a rare exception. These authors used a crown ether as scaffold to which two thiol-groups were fixed as catalytic functions. The artificial enzyme thus resembled a miniature organic model of the antibiotic synthetases which function as catalysts in nonribosomal peptide biosynthesis.29 The educts, i.e., the carboxyl- and the amine component, were covalently linked by chemical means to the enzyme mimic via thioester bonds (Figure 2). Intramolecular aminolysis resulted in the formation of a peptide bond with the growing peptide chain still bound to the carrier through a thioester linkage. After successive rounds of amino acid addition the completed tetrapeptide was finally cleaved from the crown ether by methanolysis. Although the binding of the substrates to the enzyme mimetic involved purely chemical steps, the respective peptide-bond-forming processes can be regarded as being enzyme-catalyzed. Consequently, the outcome of this study is encouraging and should stimulate further efforts in this field.
Two-Dimensional Nanomaterials for Drug Delivery in Regenerative Medicine
Published in Harishkumar Madhyastha, Durgesh Nandini Chauhan, Nanopharmaceuticals in Regenerative Medicine, 2022
Zahra Mohammadpour, Seyed Morteza Naghib
Transition metal dichalcogenides (TMDs) are another class of 2Dnanomaterials, which have widely been used in biomedicine. Biocompatibility, high photothermal conversion efficiency, and enzyme-mimic property are among several merits that give TMDs unprecedented capabilities in biomedicine. Liu et al. proposed an enzyme-responsive nanosystem to fight drug-resistant bacteria (Liu et al. 2019b). In their design, mesoporous ruthenium nanoparticles were loaded with ascorbic acid (AA) and coated with HA. In response to an enzyme called Hyal from the bacteria, the HA coating was degraded and AA was released. H2O2, as a pro-drug of AA, was converted to toxic hydroxyl radicals by the peroxidase mimic activity of MoS2 nanosheets. The chemotherapeutic effect was synergised with the photothermal property of ruthenium nanoparticles. In vivo results of wound healing proved the efficiency of the chemo/phototherapeutic system within ten days of treatment. In an attempt to develop biomaterial scaffolds, Jaiswal et al. fabricated self-assembled nanocomposite hydrogels driven by the atomic vacancies in the structure of MoS2 nanoassemblies (Jaiswal et al. 2017). The chemically cross-linked hydrogels consisted of defect-rich MoS2 and polymeric binders. The atomic vacancies in the MoS2 structure acted as an active site for the chemisorption of thiolated PEG. The gelation proceeded without UV exposure or the use of chemical initiators. Therefore, it provided a safe and non-toxic strategy to encapsulate cells in the hydrogels. More than 85% of cell viability was observed after encapsulation. The authors proposed that the vacancy-driven gelation process is a facile route for the preparation of bioactive hydrogels for use in regenerative medicine and therapeutic delivery. A summary of the applications of 2D nanomaterials in regenerative medicine is given in Table 2.1.
Biomimetic phototherapy in cancer treatment: from synthesis to application
Published in Drug Delivery, 2021
Yifan Zhao, Cuixia Shi, Jie Cao
In addition to the design of natural enzymes, some materials with enzyme-mimic activity have received increasing attention due to their unique advantages. For instance, Pt NPs can combine with other drugs and demonstrate excellent ability to catalyze H2O2. Based on this, researchers tried to develop novel types of Pt-based inorganic tumor phototherapy materials (Wei et al., 2018). One work worth mentioning is reported by Wang’ group (Wang et al., 2018). They produced a hybrid core-shell nanoplatform, with polydopamine as the core, Pt NPs interlayer, and zirconium porphyrin (PCN) as the shell. Pt NPs exhibit enzyme-mimic activity and can catalyze endogenous H2O2 to form O2. In the presence of light irradiation, O2 is then converted into ROS by zirconium porphyrin layer, thus enhancing the effectiveness of PDT (Figure 10). In vitro and in vivo studies have shown that the system can treat tumors more effectively by synergistically enhancing the regulation of PDT and TME. The study not only enriches the application of Pt-based nanomaterials in cancer treatment, but also provides guidance for the design of other nanosystems to treat cancer.
Circumventing antimicrobial-resistance and preventing its development in novel, bacterial infection-control strategies
Published in Expert Opinion on Drug Delivery, 2020
Tianrong Yu, Guimei Jiang, Ruifang Gao, Gaojian Chen, Yijin Ren, Jian Liu, Henny C. van der Mei, Henk J. Busscher
Nano-antimicrobials can be separated into two classes, based on whether composed of inorganic or organic components. Some inorganic nano-antimicrobials possess enzyme-mimic activity, like peroxidase- or deoxyribonuclease-like activity. Peroxidase-activity of inorganic nanoparticles, including carbon dots and metals included in nanocrystals, allows conversion of H2O2 into reactive-oxygen species (ROS). ROS is lethal to most bacterial strains and species [31–33], but as a drawback many ROS species are highly unstable and short-lived (usually in the micro- to milli-seconds range) [34]. Other reactive-nitrogen species generated by nanoparticles such as nitric oxide (NO) are more stable than ROS [35], killing bacteria through inhibition of DNA replication or blocking their respiration [36], and hindering adhesion [37]. Deoxyribonuclease-like activity can cause hydrolysis of extracellular DNA (eDNA) [38], an essential component of the extracellular matrix that keeps a biofilm together [39]. Disruption of the biofilm matrix may make a biofilm more amenable to antimicrobial treatment [40] and bacterial dispersal [41] into the bloodstream, after which planktonic, infectious bacteria are more prone to killing by antibiotics or host immune cells [42].
Design, synthesis and characterization of enzyme-analogue-built polymer catalysts as artificial hydrolases
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Divya Mathew, Benny Thomas, Karakkattu Subrahmanian Devaky
Regeneration of biomolecules is difficult and limited; they lose their activity within few reuse cycles, which leads to discrepancy in accuracy and increases cost per analysis. But, the molecular imprints – the artificial receptors have high physico-chemical stability towards various external degrading factors. The functional groups MIPs – the highly appealing alternatives – can easily be regenerated without loss of affinity, and hence are highly useful for continuous use. The reusability of the spent amidase MIP was investigated by our group by carrying out the amidolytic reaction after regenerating the polymer [63]. The rate acceleration of the reaction was evaluated for each cycle. The activity of the fresh mimic was considered as the control with 100% activity. It was observed that mimic regenerated could be used for five cycles of amidolysis without much loss in catalytic activity. After the fifth cycle, a reduction in catalytic activity of only 5% was observed which can be explained as mainly due to the deformation of some of the substrate recognition sites. Reusability makes the enzyme mimic more economic.