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Hydrolytic Enzymes for the Synthesis of Pharmaceuticals
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Sergio González-Granda, Vicente Gotor-Fernández
As mentioned in a previous section, the amidase activity of microorganisms is responsible of the hydrolysis of amides into carboxylic acids, which is a very useful transformation. Alternatively, some microorganisms displayed nitrilases or nitrile hydratase-amidase activities for converting cyano groups in carboxylic acids, representing in some cases an alternative synthetic solution for the production of carboxylic acids. One example is the use of the Rhodococcus rhodochrous SP 361 microorganism from Novozymes, which was able to catalyse the formation of O-protected and unprotected (R)-3-hydroxy-4-cyanobutanoic acids (Scheme 9.18). The results for the desymmetrisation of the dinitriles were highly dependent on the C-2-functionality in terms of activity and selectivity (Kinfe et al., 2009). These compounds are valuable precursors in the synthesis of the blockbuster Atorvastatin, marketed by Pfizer as a calcium salt under the trade name of Lipitor®, drug used as HMG-CoA reductase inhibitor for lowering blood cholesterol preventing cardiovascular diseases. Cyano-converting microorganism for the synthesis of (R)-3-hydroxy-4-cyanobutanoic acid and derivatives through selective nitrile hydrolysis.
B
Published in Caroline Ashley, Aileen Dunleavy, John Cunningham, The Renal Drug Handbook, 2018
Caroline Ashley, Aileen Dunleavy, John Cunningham
Brivaracetam is mainly metabolised by hydrolysis of the amide moiety to form the corresponding carboxylic acid (approximately 60% the elimination), and secondarily by hydroxylation on the propyl side chain (approximately 30% the elimination). The hydrolysis of the amide moiety leading to the carboxylic acid metabolite (34% of the dose in urine) is supported by hepatic and extra-hepatic amidase. The metabolites are inactive.
General toxicology
Published in Timbrell John, Study Toxicology Through Questions, 2017
Figure: Answer 9. Conjugation with #*glucuronic acid or *sulphate. (a) Azoreductase; (b) esterase/amidase; (c) N-acetyltransferase; (d) cytochrome P450; (e) epoxide hydrolase; (f) glutathione-S-transferase; (g) r-glutamyltransferase; (h) glycinase; (i) acetyltransferase. A10. The data in the table show that in both rats and mice the proportion of the dose of estragole metabolised to 1-hydroxyestragole increases as the dose of estragole given is increased, i.e. the metabolism is dose dependent. Therefore at the high doses used the production of the metabolite is increased. In the human, the proportion metabolised is even less, being only of the dose. Therefore with an intake of , the amount of 1-hydroxyestragole to which the human is exposed will be . The amount produced by mice at the carcinogenic dose will be of . Therefore the dose ratio between the two species based on the metabolism is . In other words, the mouse produces 10,000 million times more proximate carcinogenic metabolite at the carcinogenic dose than humans do at the expected dose.
Transition state analogue imprinted polymers as artificial amidases for amino acid p-nitroanilides: morphological effects of polymer network on catalytic efficiency
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Divya Mathew, Benny Thomas, K. S. Devaky
A typical property of enzymes is the inhibition by certain molecules. An artificial amidase MIP should show competitive inhibition by the template. A direct measurement of catalysis to occur inside the imprinted cavity can obtained from the competitive inhibition of TSA in the amidolysis catalyzed by the amidase MIPs and NIPs [27,28]. The TSA inhibition studies were carried out in the amidolytic reaction in the presence of the phosphonate TSA using the polymer catalysts C1–C3. As shown in Figure 8, the amidase activity of the amidase MIPs was fairly inhibited, as the concentration of the template TSA was increased due to “the shape-selective rebinding” of the imprinted TSA over the substrate S1. This would be a further proof for catalysis to occur inside the imprinted cavity. In this respect, the catalytic the amidolysis of S1 was stopped completely under the condition of [TSA]/[S1] = 2.0, 3.0 and 1.0 for the polymers C1, C2 and C3, respectively. A better rebinding within shorter time is observed for C3 due to solvent memory of the polymer catalyst. There are reports on the solvent memory of polymers in the template rebinding studies. Molecularly imprinted polymers always exhibit maximum recognition capacity when the same porogen is used as the preparation and selectivity studies. The use of other solvents will cause destruction of the 3D structure of the imprints which are shape-complementary to the target molecule. It is notable that MIPs prepared in organic solvent work poorly in aqueous media because of the “solvent memory” [21].
Doxorubicin-conjugated D-glucosamine- and folate- bi-functionalised InP/ZnS quantum dots for cancer cells imaging and therapy
Published in Journal of Drug Targeting, 2018
Zahra Ranjbar-Navazi, Morteza Eskandani, Mohammad Johari-Ahar, Ali Nemati, Hamid Akbari, Soudabeh Davaran, Yadollah Omidi
The release profile of doxorubicin was studied using UV-Vis spectrophotometry at the maximum wavelength of 490 nm in PBS buffer (pH = 7.4 and pH = 5, 37 °C) and compared with the calibration curve of doxorubicin. No evident release was observed in the neutral condition (pH = 7.4). Besides, as shown in Figure 7, the drug released in acidic medium (pH = 5.5) was negligible, in large part due to the stable amide bonds between QDs surface carboxylic groups and doxorubicin molecules. In fact, amide bond breaking needs amidase enzyme expressed in cells and many tissues. As a result, physiological conditions were required for doxorubicin release, and accordingly, the cytotoxicity results confirmed the efficient pharmacological effect of doxorubicin-conjugated functionalised QDs indicating the release of doxorubicin due to the enzymatic destruction of amid bounds between drug and QDs in vitro.
Clostridioides difficile: innovations in target discovery and potential for therapeutic success
Published in Expert Opinion on Therapeutic Targets, 2021
Tanya M Monaghan, Anna M Seekatz, Benjamin H Mullish, Claudia C. E. R Moore-Gillon, Lisa F. Dawson, Ammar Ahmed, Dina Kao, Weng C Chan
Bacteriophage are bacterial viruses, which can infect and kill certain bacteria. Phage have a narrow host range, which makes them a potentially useful therapeutic to target specific pathogenic bacteria [55]. There are main two types of phage, lytic and temperate. Temperate phage have the capacity to be either lytic or lysogenic depending on the host and environmental conditions, however only lytic phage show therapeutic potential. To date, a limited number of C. difficile specific lytic phage have been identified. Phage produced endolysins/lysins rapidly degrade cell wall peptidoglycan to facilitate release of bacteriophage progeny following replication [56]. Bacteriophage-derived endolysins and their derivatives have shown efficacy as a novel class of antibacterial agents. C. difficile bacteriophages produce amidase and endolysin. Mondal et al. [57] identified that recombinantly expressed cell wall hydrolase (CWH) lysin from C. difficile phage, phiMMP01, was active against C. difficile and this activity could be enhanced by removing the N-terminal cell wall binding domain, creating CWH351 – 656 [57]. Interestingly, Mayer et al. [58], identified that truncation of the endolysin CD27L from phage ΦCD27, retaining just the N-terminal domain, CD27L1–179, increased lytic activity against C. difficile [58]. This recombinant CWH (CWH351 – 656) inhibits spore outgrowth in vitro, which the authors suggest is critical in preventing the spread and recurrence of C. difficile infection [57]. Phage lytic enzymes have been shown to achieve a 4-log reduction in C. difficile vegetative cell viability in 5 hours after external application [59], potentially making them a narrow spectrum target for CDI. However, the lack of naturally occurring strictly lytic phages in C. difficile has significantly impacted phage therapy [60], but the use of recombinant lytic phage protein has opened a door for targeted phage therapy.