Metal ion complexes of antivirally active nucleotide analogues. Conclusions regarding their biological action.
Acyclic nucleoside phosphonates (ANPs), i.e., analogues of (2'-deoxy)nucleoside 5'-monophosphates, have been studied during the past 15 years for their potential as antiviral drugs. One of these compounds, 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA; Adefovir) was recently approved in the form of its bis(pivaloyloxymethyl)ester (Adefovir dipivoxil) for use in hepatitis B therapy, a disease evoked by a DNA virus. Diphosphorylated PMEA(2-), i.e., PMEApp(4-), is initially recognized by nucleic acid polymerases as an excellent substrate, but after insertion in the growing nucleic acid chain, this is terminated due to the lack of a 3'-hydroxy group. Based on the metal ion-binding properties of PMEApp(4-) it can be explained why the ether oxygen in the aliphatic chain, R-CH(2)-O-CH(2)-PO(3)pp(4-), is compulsory for a useful biological activity. Consequently, this critical review presents an overview on the coordination chemistry of various ANPs and correlates this to their biological properties.
Sigel
Helmut
H
Department of Chemistry, Inorganic Chemistry, University of Basel, Spitalstrasse 51, CH-4056 Basel, Switzerland. Helmut.Sigel@unibas.ch
D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000227:Adenine Nucleotides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004355:Drug Stability; D006801:Humans; D007477:Ions; D008670:Metals / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D009711:Nucleotides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D063065:Organophosphonates; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014779:Virus Replication / Q000187:drug effects
D000227:Adenine Nucleotides; D000998:Antiviral Agents; D007477:Ions; D008670:Metals; D009711:Nucleotides; D063065:Organophosphonates; C053001:adefovir; D000225:Adenine