title: [Anti-retroviral activity and molecular-biochemical action mechanism of 2',3'-dideoxynucleoside analogs and 9-(2-phosphonylmethoxyethyl) purine derivatives].
abstract: The antiviral mechanism of action and intracellular metabolism of 2',3'-dideoxycytidine (ddCyd), 3'-azido-2',3'-dideoxythymidine (AZT) and 2',3'-didehydro-2',3'-dideoxythymidine (D4T) has been investigated. Marked differences in the affinity of these anti-HIV compounds for their activating (phosphorylating) enzymes, and the eventual intracellular levels of their active 5'-triphosphate metabolites were discovered. Moreover, new approaches were developed to manipulate the metabolism of these products in such a way that combination of ddCyd with thymidine, and 2',3'-dideoxynosine with ribavirin resulted in an enhanced antiretroviral effect of the test compounds in vitro and/or in vivo. Several metabolic and kinetic properties of AZT and D4T proved highly relevant to perform or modify the treatment modalities of AIDS patients with these chemotherapeutics. A novel class of acyclic purine nucleotide phosphonate derivatives endowed with potent and selective anti-HIV activity has been developed. The prototype compound is 9-(2-phosphonylmethoxyethyl)adenine (PMEA). PMEA proved to have a potent antiretroviral activity in a number of retrovirus models in vivo. Furthermore, a unique administration schedule of PMEA in retrovirus infections has been proposed, in which the antiretroviral properties of PMEA are clearly superior and distinguished from those of other chemotherapeutics such as AZT. The metabolic and kinetic properties of PMEA and its phosphorylated metabolites have been investigated. Our data provide a better and profound insight in the antiretroviral activity and the molecular and biochemical bases for the mechanism or action of the drug.
authors.affiliation: K.U.L.-Rega Instituut, Leuven, België.
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D010766:Phosphorylation; D011741:Pyrimidine Nucleosides / Q000627:therapeutic use; D012190:Retroviridae / Q000187:drug effects*; D012254:Ribavirin / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D016047:Zalcitabine / Q000627:therapeutic use; D015215:Zidovudine / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D011741:Pyrimidine Nucleosides; D012254:Ribavirin; D015215:Zidovudine; D016047:Zalcitabine; D000225:Adenine
vernacular_title: Antiretrovirale activiteit en moleculair-biochemisch werkingsmechanisme van 2',3'-dideoxynucleoside analogen en 9-(2-fosfonylmethoxyethyl)purine derivaten.