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The Fight Against Cancer
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
This method has advantages over antibody-drug therapy. Enzymes are catalytic, so can generate a large number of active drug molecules at the tumour site, which diffuse into the tumour and may also target cancer cells in this region that do not display the necessary antigens for antibody binding. The use of foreign enzymes derived from bacteria circumvents the problems that would arise if a mammalian enzyme was to be used, which could result in similar enzymes within the body activating the highly cytotoxic prodrug in healthy tissue.
On Biocatalysis as Resourceful Methodology for Complex Syntheses: Selective Catalysis, Cascades and Biosynthesis
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Andreas Sebastian Klein, Thomas Classen, Jörg Pietruszka
As we have illustrated, in vitro biocatalysis offers a wide range of options to exploit the extraordinary selectivity of many enzymes. Synthesis routes can be streamlined and thus the biocatalytic routes might be more efficient. In this chapter the emphasis was not on the in vitro catalysis methodology, but provided selected examples, only. For further reading, a recent review (Classen and Pietruszka, 2017) is recommended. In the following sections, we focus on in vivo biocatalysis and highlight these advanced techniques, which may grant access to complex natural target structures as well as derivatives thereof.
Framework
Published in Peter W. Hochachka, Muscles as Molecular and Metabolic Machines, 2019
For over 15 years, it has been postulated that hexokinase binding to the mitochondria serves two key processes: (i) speeding up catalysis by activating the enzyme (reducing product inhibition) and (ii) supplying a direct (controllable) route for ATP formed at the ATP synthase to the hexokinase for glucose phosphorylation, which would be advantageous during high rates of glucose catabolism. While accepting this overall model of mitochondrial hexokinase function, recent workers (Wicker et al., 1993) suggest that, because of the relatively high concentration of ATP expected at this site compared to a relatively low [ADP], an additional crucial function of this hexokinase localization is to assure a flow of ADP to the adenylate transolase (for inward flux towards the mitochondrial ATP synthase). This highly attractive hypothesis thus implies a kind of two enzyme (CPK and HK) conduit symmetry around the adenylate translocase: CPK receiving ATP from adenylate translocase and serving as the first main sink for ATP formed in mitochondrial metabolism and hexokinase serving as a kind of catalytic backup reaction, assuring an added constant flux of ADP back to the adenylate translocase to coordinate glucose catabolic rates with oxidative phosphorylation rates.
Advances in biocatalytic and chemoenzymatic synthesis of nucleoside analogues
Published in Expert Opinion on Drug Discovery, 2022
Sebastian C. Cosgrove, Gavin J. Miller
Biocatalysis has, however, advanced to a point where enzymes can now be designed to be the perfect catalyst for a particular process [5]. The advent of directed evolution in the early 1990s revolutionized how chemists approached enzymatic transformations, with pioneers such as Arnold demonstrating how artificial evolutionary pressure could transform the function of a protein in extremely short timeframes [6]. Technological advances since then, in particular the power of computation to help understand protein dynamics and the significant reduction in the cost of DNA technologies (e.g., synthesis and sequencing), have delivered a myriad of methods for the efficient evolution of enzymes for synthetic chemistry. A landmark study involved engineering of a transaminase to synthesize the blockbuster diabetes treatment sitagliptin [7]. This enzyme underwent multiple rounds of evolution to deliver a mutant that could operate under conditions akin to that of a synthetic catalyst (200 g L−1 substrate loading, 50% DMSO v/v, 1 M amine donor) and deliver the final amine with perfect stereocontrol. What this study demonstrated was how enzymes could be pushed to function well beyond their natural limits, but still under ambient conditions with perfect selectivity obtained from natural evolution.
Nanoparticles in nanomedicine: a comprehensive updated review on current status, challenges and emerging opportunities
Published in Journal of Microencapsulation, 2021
Heidi Mohamed Abdel-Mageed, Nermeen Zakaria AbuelEzz, Rasha Ali Radwan, Saleh Ahmed Mohamed
Intriguingly, nanoparticles with ‘enzyme-mimetic’ activity have been studied as alternatives to natural enzymes. Catalytically active nanomaterials specifically in Nanohybrid iron oxide NP formulation and preparation allowed the introduction of enzyme mimetics, possessing peroxidase, oxidase, superoxide dismutase and catalase-like activities (nanozymes) (Singh 2019). The field of nanozymes offers promising new biomedical applications, from biofilm disruption to neurodegeneration protection and cancer prevention however, it is still in its infancy (Cormode et al.2018). Studies published are remarkable nonetheless several questions still are unanswered, which endorses further research pursue. The interwoven relationship between catalytic efficiency, therapeutic activity and biocomptability is yet to be resolved. High-performance nanozymes and highly selective nanozymes are to be developed to match catalytic efficiency natural enzymes. Also problems with batch-to-batch variation in size and shape of nanoparticles/nanozymes, and thus variations in physicochemical characteristics, demands more emphasis on optimising the synthesis protocol for production of monodispersed nanozymes. In view of the discussed points it is evident that nanomedicine research arena is yet to fully mature to revolutionise the field of human medicine. High demand of investments, scientific and technical limits and overfilling sellers and marketing challenges such as excessive therapeutics prices and limited market penetration are obstacles that demand attention to enhance the potential of nanoparticle drug delivery share.
Enzyme therapy: a forerunner in catalyzing a healthy society?
Published in Expert Opinion on Biological Therapy, 2020
Saptashwa Datta, K Narayanan Rajnish, C George Priya Doss, S. Melvin Samuel, E. Selvarajan, Hatem Zayed
The main problem with most current cancer treatment methods is the lack of specificity of the treatments. The available treatments not only destroy cancer cells but also destroy the healthy cells surrounding the tumor, which leads to many complications. However, with recent advancements, one of the major new treatments involves the use of enzymes. Enzyme therapy in cancer has been applied in two different ways. In the first approach, a prodrug bound to an enzyme is directed to a specified site, and the enzyme is released only when the localized region is reached; there, the prodrug is converted into an active drug that then induces cell apoptosis. This method is known as enzyme prodrug therapy. The other approach is called antibody-mediated enzyme prodrug therapy (ADEPT). In this procedure, an enzyme is tagged to a partial or whole antibody that is specific to a tumor antigen. This results in catalysis of certain reactions inside the cell that lead to cell apoptosis. The toxic enzymes include oxidases, such as glucose oxidase, that can catalyze the formation of peroxide from glucose. However, the complexity of the system, the pharmacokinetics of the drug and enzyme and the characterization and availability of antigens are major drawbacks for these systems [106].