Phosphoramidates composed of an amino acid and anucleotide analogue are critical metabolites of prodrugs,such as remdesivir.Hydrolysis of the phosphoramidate liberates the nucleotide,w hichc an then be phosphorylated to become the pharmacologically active triphosphate.E nzymatic hydrolysis has been demonstrated, but as pontaneous chemical process may also occur.W em easured the rate of enzyme-free hydrolysis for 17 phosphoramidates of ribonucleotides with amino acids or related compounds at pH 7.5. Phosphoramidates of proline hydrolyzed fast, with ahalf-life time as short as 2.4 hf or Pro-AMP in ethylimidazole-containing buffer at 37 8 8C; 45-fold faster than Ala-AMP and 120-fold faster than Phe-AMP.C rystal structures of Gly-AMP,P ro-AMP, bPro-AMP and Phe-AMP bound to RNase Aa sc rystallization chaperone showed how well the carboxylate is poised to attack the phosphoramidate,h elping to explain this reactivity.O ur results are significant for the design of new antiviral prodrugs.
List of abbreviations: AEDs -antiepileptic drugs, 8 -epi-PGF 2a -urinary isoprostanes, GPX -glutathione peroxidase, ILAE -International League Against Epilepsy, 8-OHdG -8-hydroxy-2'-deoxyguanosine, P-SH -protein thiol groups, RCD -reactive carbonyl derivatives, ROS -reactive oxygen species, SOD -superoxide dismutase. SummaryBackground: To get more insight into the effects of the most widely used antiepileptic drugs (AEDs) on the pro oxi dant/ antioxidant balance in epi lep sy, a comparative analysis of the byproducts of oxidative damage and antioxidant de fense mechanisms was performed in patients with epilepsy treated with la mo trigine, carbamazepine and valproic acid. Methods: Byproducts of oxidative damage to proteins (reactive carbonyl derivatives, RCD and protein thiol groups, P-SH), lipids (urinary isoprostanes, 8 -epi-PGF 2a ) and DNA (urinary 8-hydroxy-2'-deoxyguanosine, 8-OHdG), as well as the activities of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPX) were measured in 60 patients with newly diagnosed seizure (at illness onset and after 6 months of treatment with lamotrigine, carbamazepine or valproic acid) and in 20 healthy controls. Results: In patients with epilepsy, RCD, urinary 8-epi-PGF 2a and 8 -OHdG, together with SOD and GPX activities were significantly increased, while P-SH were only slightly decreased. After 6 months of treatment with AEDs, a decrease was observed in RCD, urinary 8-epi-PGF 2a and 8-
Phosphoramidates composed of an amino acid and anucleotide analogue are critical metabolites of prodrugs,such as remdesivir.Hydrolysis of the phosphoramidate liberates the nucleotide,w hichc an then be phosphorylated to become the pharmacologically active triphosphate.E nzymatic hydrolysis has been demonstrated, but as pontaneous chemical process may also occur.W em easured the rate of enzyme-free hydrolysis for 17 phosphoramidates of ribonucleotides with amino acids or related compounds at pH 7.5. Phosphoramidates of proline hydrolyzed fast, with ahalf-life time as short as 2.4 hf or Pro-AMP in ethylimidazole-containing buffer at 37 8 8C; 45-fold faster than Ala-AMP and 120-fold faster than Phe-AMP.C rystal structures of Gly-AMP,P ro-AMP, bPro-AMP and Phe-AMP bound to RNase Aa sc rystallization chaperone showed how well the carboxylate is poised to attack the phosphoramidate,h elping to explain this reactivity.O ur results are significant for the design of new antiviral prodrugs.
The role of nitric oxide (NO) in neurological diseases represents one of the most studied, yet controversial subjects in physiology. The aim was to examine the effects of intrastriatal injection neurotrophins (nerve growth factors-NGF, fibroblast growth factors-FGF) in order to investigate the possible involvement of NO in quinolinic acid (QA) induced striatal toxicity in the rat model of Huntington's disease (HD). QA was administered unilaterally into the striatum of adult Wistar rats in a single dose of 150 nM. The other two groups of animals were pretreated immediately before QA application with NGF and FGF, respectively. Control group was treated with 0.9% saline solution in the same manner. Animals were decapitated 7 days after the treatment. Nitrite levels were significantly decreased both in the ipsi- and contralateral striatum and forebrain cortex of NGF- and FGF-treated animals compared with QA treatment. These results indicated a temporal and spatial propagation of oxidative stress and spread protective effects of NGF and FGF on the forebrain cortex, the distant structure, but tightly connected with striatum, the place of direct neurotoxic damage. Neurotrophins could be the potential neuroprotective agents in HD.
In the present study we employed Nw-nitro-L-arginine methyl ester, non-specific potent nitric oxide synthase inhibitor and a selective inhibitor of neuronal nitric oxide synthase, 7-nitroindazole, reportedly to investigate the possible involvement of nitric oxide in quinolinic acid-induced striatal toxicity in the rat. Quinolinic acid was administered unilaterally into striatum of adult Wistar rats in the single dose of 150 nmol/L. The other two group of animals were pretreated with Nw-nitro-L-arginine methyl ester and 7-nitroindazole respectively. Control groups of animals were treated with 0,154 mmol/L saline solution likewise. Nitrite levels was decreased in the ipsi- and contralateral striatum and forebrain cortex in the group treated with nitric oxide synthase inhibitors and neurotoxin compared to quinolinic acid-treated animals. In the same structures, activity of glucose-6-phosphate dehydrogenase was also decreased, compared to quinolinic acid-treated animals. These results indicate that application of the nitric oxide synthase inhibitors, supressed nitrite accumulation and glucose-6-phosphate dehydrogenase activity and attenuated quinolinic acid-induced neuronal damage in the striatum and forebrain cortex.
The aetiology of neuronal death in neurodegenerative diseases, including Huntington's disease, is still unknown. There could be a complex interplay among altered energy metabolism, excitotoxicity and oxidative stress. Our aim was to examine the effects of intrastriatal injection of a selective inhibitor of neuronal nitric oxide synthase, 7-nitroindazole, and a non-specific potent nitric oxide synthase inhibitor, Nw-nitro-L-arginine methyl ester, in order to study the possible involvement of glutathione, an important antioxidant, in quinolinic acid-induced striatal toxicity in the rat. Unilateral administration of quinolinic acid to rat striatum in a single dose of 150 nmol/L was used as a model of Huntington's disease. The other group of animals were pretreated with 7nitroindazole and Nw-nitro-L-arginine methyl ester, respectively. Control groups were treated with saline solution and olive oil, respectively. Content of total glutathione, was increased in the ipsi-and contralateral striatum, forebrain cortex, basal forebrain and hippocampus in the groups treated with nitric oxid synthase inhibitors and quinolinic acid compared to the quinolinic acid-treated animals. These results support the hypothesis that oxygen free radicals contribute to excitotoxic neuronal injury, and also that nitric oxide synthase inhibitors could be potential neuroprotective agents in Huntington's disease.
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