title: The predominant mechanism by which ribavirin exerts its antiviral activity in vitro against flaviviruses and paramyxoviruses is mediated by inhibition of IMP dehydrogenase.
abstract: It is not yet clear to what extent depletion of intracellular GTP pools contributes to the antiviral activity of ribavirin. Therefore, the antiviral activities of (i) ribavirin, (ii) its 5-ethynyl analogue, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR), and (iii) mycophenolic acid (MPA) (a compound that inhibits only cellular IMP dehydrogenase activity) were studied on the replication of flaviviruses and paramyxoviruses. In addition, the effects of these three compounds on intracellular GTP pools were assessed. A linear correlation was observed over a broad concentration range between the antiviral activities of ribavirin, EICAR, and MPA and the effects of these compounds on GTP pool depletion. When the 50% effective concentrations (EC50s) for the antiviral activities of ribavirin, EICAR, and MPA were plotted against the respective EC50 values for GTP pool depletion, a linear correlation was calculated. These data provide compelling evidence that the predominant mechanism of action of ribavirin in vitro against flavi- and paramyxoviruses is based on inhibition of cellular IMP dehydrogenase activity.
authors.affiliation: Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Leyssen
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D006160:Guanosine Triphosphate / Q000378:metabolism; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D008826:Microbial Sensitivity Tests / Q000379:methods; D009173:Mycophenolic Acid / Q000737:chemistry / Q000494:pharmacology; D010224:Parainfluenza Virus 3, Human / Q000187:drug effects* / Q000201:enzymology; D012254:Ribavirin / Q000737:chemistry / Q000494:pharmacology*; D012263:Ribonucleosides / Q000737:chemistry / Q000494:pharmacology; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects; D015005:Yellow fever virus / Q000187:drug effects* / Q000201:enzymology
chemical_list: D000998:Antiviral Agents; D012263:Ribonucleosides; C059077:5-ethynyl-1-ribofuranosylimidazole-4-carboxamide; D012254:Ribavirin; D006160:Guanosine Triphosphate; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid