ganciclovir brands

Molecular formula: C9H13N5O4

Ganciclovir's antiviral activity inhibits virus replication. This inhibitory action is highly selective as the drug must be converted to the active form by a virus-encoded cellular enzyme, thymidine kinase (TK). TK catalyzes phosphorylation of ganciclovir to the monophosphate, which is then subsequently converted into the diphosphate by cellular guanylate kinase and into the triphosphate by a number of cellular enzymes. <i>In vitro</i>, ganciclovir triphosphate stops replication of herpes viral DNA. When used as a substrate for viral DNA polymerase, ganciclovir triphosphate competitively inhibits dATP leading to the formation of 'faulty' DNA. This is where ganciclovir triphosphate is incorporated into the DNA strand replacing many of the adenosine bases. This results in the prevention of DNA synthesis, as phosphodiester bridges can longer to be built, destabilizing the strand. Ganciclovir inhibits viral DNA polymerases more effectively than it does cellular polymerase, and chain elongation resumes when ganciclovir is removed. Although the exact mechanism(s) of action of ganciclovir has not been fully elucidated, it appears that the drug exerts its antiviral effect on human cytomegalovirus and the other human herpesviruses by interfering with DNA synthesis via competition with deoxyguanosine for incorporation into viral DNA and by being incorporated into growing viral DNA chains. The active phosphorylated form of ganciclovir can both competitively inhibit viral DNA polymerase and be incorporated into growing DNA chains as a false nucleotide, thus interfering with chain elongation (prematurely terminating DNA synthesis) and/or resulting in formation of a mutant DNA chain and thereby inhibiting viral replication. Ganciclovir triphosphate apparently has no effect on viral protein or RNA synthesis. Cellular alpha-DNA polymerase also is inhibited by the drug, but generally at concentrations higher than those required for inhibition of viral DNA polymerase. In human bone marrow cells, the IC50 (concentration of drug that produces 50% inhibition of cell division) has been reported as 9.95 ug/ml. Unchanged ganciclovir does not appear to possess antiviral activity. Instead, the antiviral activity appears to depend principally on intracellular conversion of the drug to ganciclovir triphosphate. The formation of ganciclovir monophosphate appears to be the rate limiting step in the formation of ganciclovir triphosphate. In vitro in herpes viruses, ganciclovir triphosphate functions both as substrate for, and a preferential inhibitor of, viral DNA polymerase and as a false nucleotide base. In cells infected with herpes simplex virus type 1 or 2 or varicella-zoster virus, ganciclovir is converted to ganciclovir monophosphate via virus-coded thymidine kinase. The pathway for conversion to the monophosphate in cells infected with Epstein-Barr virus or cytomegalovirus is unclear; these viruses do not code for thymidine kinase, and a cellular deoxyguanosine kinase, found in the cytosol and in mitochondria, may be involved. In cytomegalovirus infected cells, increased concentrations of deoxyguanosine kinase (mitochondrial origin) have been detected, suggesting that the virus may induce production of the enzyme. Subsequent phosphorylation occurs via cellular kinases (including guanylate kinase, phosphoglycerate kinase, and nucleoside diphosphate kinase) to the diphosphate and then the active triphosphate form. Ganciclovir appears to be principally virustatic rather than virucidal in action. Following removal of the drug from the culture medium in vitro, viral DNA synthesis, which previously was inhibited, resumes, resulting in restored viral replication. In addition, clinical evidence of reactivated disease suggests that ganciclovir acts principally to suppress virus activity and that eradication of the virus does not appear to occur.

Source: PubChem (NCBI) · compound 135398740