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Antiviral therapeutics for viral infections of the central nervous system
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
Ganciclovir is phosphorylated to the monophosphate derivative by a cellular deoxyguanosine kinase more rapidly in infected than uninfected cells. HSV and VZV TK monophosphorylate ganciclovir after which it is further metabolized to the active triphosphate by cellular enzymes. The UL97 open-reading frame of CMV encodes a phosphonotransferase, which can regulate phosphorylation. In CMV-infected cells the concentration of the triphosphate is approximately 10-fold higher than in uninfected cells. The ID50 for CMV ranges from 0.5 to 11 μmol (0.125–2.75 mg/L). EBV is inhibited by 1–4 μmol and VZV by 4–40 μmol. The activity against HHV-6 and HHV-7 is similar to EBV [25].
Instability of Human Mitochondrial DNA, Nuclear Genes and Diseases
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
In mitochondria the salvation pathway is the most important even crucial for mtDNA maintenance and absence of TK2 or dGK leads to severe clinical consequences. Mutations in TK2 encoding thymidine kinase (2p13.1) and DGUOK encoding deoxyguanosine kinase (16q21) are responsible for depletion syndrome. In case of DGUOK it is again a hepatocerebral type with very early onset and poor outcome. Mutations in TK2 lead to the myopathic type of depletion syndrome with muscle weakness and hypotonia and variable age of onset from childhood to adulthood. They can also be responsible for PEO with multiple large-scale mtDNA deletions. All pathogenic variants both in DGUOK and TK2 regardless of the phenotype they manifest are recessive36,37.
The mitochondrial DNA depletion syndromes: mitochondrial DNA polymerase deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
In the period since the initial description [1], more than 50 patients have been reported [8]. A diagnosis of mitochondrial DNA depletion may be suspected on the basis of fasting hypoglycemia and liver dysfunction characterized by elevations of gamma glutamyl transferase (GGT), often greater than alanine aminotransferase (ALT) and aspartate aminotransferase (AST), or by elevated CK and ragged red fibers. It is confirmed by quantitative analysis of mitochondrial DNA in biopsied tissue or, in the case of the hepatic toddler form, by demonstration of mitochondrial DNA polymerase deficiency. In the early infantile-onset hepatocerebral disease, a mutation in the deoxyguanosine kinase gene on chromosome 2p13 has been identified [9]. In addition to this single base deletion in the dGK (DGUOK) gene, missense mutations, duplications, and other deletions have been described [10]. In four families with myopathic disease, mutations were defined in the thymidine kinase gene (TK2) on chromosome 16q22 [11]. It is clear there is heterogeneity, because only about 10 percent of patients with similar phenotypes that were tested were found to have mutations in these two deoxynucleoside kinases [10, 12, 13]. Mitochondrial DNA depletion has also been found in patients with encephalomyopathy and defects in the succinyl-CoA synthetase gene (SUCLA2) [14]. In addition, mitochondrial DNA depletion has been found in patients with mutations in the twinkle helicase gene (PEO1) [15], the adenine nucleotide translocator gene (ANT1) [16], inner mitochondrial membrane protein gene (MPV17) [16–19], and the B subunit of ribonucleotide reductase (RRM2B), as well as the thymidine phosphorylase gene (TP) in patients with mitochondrial neurogastrointestinal encephalomyelitis (MNGE). Patients with methylmalonic acidemia and mitochondrial DNA depletion have mutations in the succinate syntheses (SUCLG1) [14–19].
An overview of ProTide technology and its implications to drug discovery
Published in Expert Opinion on Drug Discovery, 2021
Michaela Serpi, Fabrizio Pertusati
Promising results of ProTide prodrugs were shown in the treatment of mitochondrial DNA (mtDNA) depletion syndrome (MDS), a group of rare autosomal-recessive diseases, characterized by reduction of mitochondrial DNA [116]. In this study, a novel ProTide of 2ʹ-deoxy guanosine nucleoside (CERC-913, structure not disclosed), designed to bypass defective mitochondrial deoxyguanosine kinase (DGUOK), showed to restore, in a dose-dependent fashion, mtDNA content in a primary hepatocyte culture model of DGUOK deficiency.