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Alternative Tumor-Targeting Strategies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The best-known example of this approach is the therapeutic use of the enzyme asparaginase, which reduces circulating concentrations of the amino acid asparagine and is used to treat leukemia patients with Acute Myeloid Leukemia (AML). Based on the success of asparaginase, other amino acid deprivation strategies have been investigated such as the use of recombinant human arginase (rhArg) for arginine deprivation therapy which is currently in clinical trials. A similar approach has been taken with the enzyme Arginine Deiminase (ADI) which catabolizes arginine to L-citrulline. These approaches are described in more detail below.
The Importance of Immune Cells in the Pathogenesis Of NEC
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Andres Gonzalez Salazar, David J. Hackam
The relationship between neutrophils (PMNs) and NEC has been studied for the past 3 decades. Musemeche et al. initially concluded an important role for PMNs in NEC by depleting neutrophils with vinblastine in a platelet activator factor (PAF) and lipopolysaccharide (LPS) rat NEC model, which decreased the severity of intestinal injury (3). The role of PMNs in NEC received little attention, given the fact that histologic and flow cytometric evaluation of the human and mouse bowel with NEC is relatively PMN deficient (1). More recently, PMNs have been linked to the development of NEC through the formation of neutrophil extracellular traps (NETs). These are web-like structures made up of DNA that contain antimicrobial proteins and histones and are formed in the presence of virus, bacteria, and protozoa, where they bind to, immobilize, and eliminate microorganisms (4, 5). Studies have suggested that an excessive NET formation is crucial in the ischemic injury that ultimately leads to neutrophilic tissue damage (4). In both animal models and human neonates suffering from NEC, studies have demonstrated an increase in intestinal cell-free DNA (cfDNA) and neutrophilic proteins, markers of NET formation (5, 6). In further support of this association, more recent studies have hypothesized that impeding or dissolving NET formation may lead to reduced tissue injury and inflammation (7, 8). Treatment of mice NEC models with DNase1 and protein arginine deiminase (PAD), inhibitors of NETs, have been shown decreased NEC severity, further supporting these claims (9, 10).
Enzymatic Amino Acid Deprivation Therapies Targeting Cancer
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Carla S. S. Teixeira, Henrique S. Fernandes, Sérgio F. Sousa, Nuno M. F. S. A. Cerqueira
Some cancers such as metastatic melanoma (MM), prostate carcinomas, hepatocellular carcinoma (HCC) (Dillon et al., 2004) non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, pancreatic carcinoma, osteosarcoma, and malignant pleural mesothelioma and some breast tumours (Qiu et al., 2015) have an elevated requirement for l-ARG due to the deficient expression of ASS1 that results in l-ARG auxotrophy (Feun et al., 2008, 2012, 2015). Arginine deiminase (ADI, EC 3.5.3.6) is an enzyme with high affinity to l-ARG that catalyses the conversion of l-ARG into citrulline and ammonia. The cancer cells who do not express ASS1 are unable to re-synthesize l-ARG from citrulline, which culminates in the full deprivation of an amino acid that is imperative for their survival (Shen et al., 2003).
A virulence factor as a therapeutic: the probiotic Enterococcus faecium SF68 arginine deiminase inhibits innate immune signaling pathways
Published in Gut Microbes, 2022
Fereshteh Ghazisaeedi, Jochen Meens, Bianca Hansche, Sven Maurischat, Peter Schwerk, Ralph Goethe, Lothar H. Wieler, Marcus Fulde, Karsten Tedin
Arginine deiminase (ADI) activities in the AS fractions of E. faecium SF68, E. avium, and E. avium transformants harboring plasmids pMGS100 or pMGS100-arcASF68, were determined from 1:5 dilutions of protein preparations in water in a total of 100 µl added to 400 µl of 0.1 M potassium phosphate buffer, pH 6.5, and 10 mM L-arginine, and the reactions were incubated at 37°C for 2 h. At the end of the incubation, the reactions were terminated by addition of 250 µl of a sulfuric acid/orthophosphoric acid stop solution and 31.3 µL of 3% diacetyl monoxime, and the samples were boiled for 15 min. at 100°C in the dark. Reactions were allowed to cool to room temperature in the dark for 10 min. and the absorption at 440 nm was determined. Reactions without addition of bacterial lysate or AS fractions served as negative (background) controls. The ADI activity of the samples was determined from a standard curve of 0 to 100 µg of citrulline performed in parallel. The final ADI activity was calculated as the as nmol citrulline/h/mg protein. For addtional details of the ADI enzymatic assays and references, see the supplementary Methods.
Targeting the integrated stress response in ophthalmology
Published in Current Eye Research, 2021
Hsiao-Sang Chu, Cornelia Peterson, Albert Jun, James Foster
Pharmacological activation of ISR signaling can be achieved by activating eIF2α kinases. Halofuginone,124 histidinol,116 asparaginase,125 and arginine deiminase126 are known to be GCN2 activators; BTdCPU activates HRI127; BEPP and poly (I:C) are PKR activators128,129; and CCT020312130,131 is a selective PERK activator. These potential drugs were mostly studied for cancer treatment, and the application in ophthalmology fields is just emerging.33,35 In vivo, oral administrated or intraperitoneal injected halofuginone has shown potent inhibitory effects on angiogenesis progression in a mouse corneal neovascularization model.132 Arginine deiminase catalyzes the deimination of proteins, a nonreversible post-translational conversion of protein-bound arginines to protein-bound citrullines. Elevated levels of protein deimination are reported in human neurological diseases,133 the retina tissue of AMD patients,134 and the optic nerve of open-angle glaucoma eyes.135 These findings suggest GCN2 may be one of the treatment targets of AMD and glaucoma. Poly (I:C), polyinosinic:poycytidylic acid, has similar structure to the double-stranded RNA which leads to PKR activation.129 In vivo, topical and systemic administrated Poly (I:C) has been known for decades to induce tear interferon against HSV in rabbit and human eyes.136,137
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
In a study from 1999, supplying proteolytic enzymes in the diet was found to help increase the lifespan of people who had pancreatic cancer. However, little can be concluded from the study because of its tiny sample size [112]. Hepacid is an intramuscularly administered polyethylene glycosylated arginine deiminase enzyme that is being developed as a treatment for hepatocellular carcinoma. Melanocid is another polyethylene glycosylated arginine deiminase-derived enzyme that is used for the treatment of metastatic melanoma. Both of these enzymes degrade and reduce the level of arginine, which is a vital amino acid that is necessary for the proliferation of malignant cells [113]. These enzymes have been observed to have a significant effect on mice; however, the use of arginine deiminase enzymes remains limited in humans owing to their short serum half-life. Moreover, as these enzymes are of microbial origin, they have been observed to have high immunogenicity in mammals. Although the enzymes have been observed to have significant effects in some patients during clinical trials, they show highly inconsistent results and have been observed to produce multiple side effects, including elevated ammonia levels. These arginine deiminase enzyme-producing genes have been isolated from bacteria such as Streptococcus sangria, Mycoplasma arginini, and Pseudomonas aeruginosa and overexpressed mostly in Escherichia coli BL21 cells [114].