Mechanism of antiviral and cytotoxic action of (+/-)-6' beta-fluoroaristeromycin, a potent inhibitor of S-adenosylhomocysteine hydrolase.
(+/-)-6' beta-Fluoroaristeromycin (F-C-Ado) is a potent and competitive inhibitor of purified S-adenosylhomocysteine (AdoHcy) hydrolase isolated from murine L929 cells (Ki = 3.1 nM). It also inhibits vaccinia virus and vesicular stomatitis virus replication in L929 cells, at a 90% inhibitory dose (ID90) of 3.5 and 13 microM, respectively. Considering the close correlation that has been found between Ki and ID90 for other AdoHcy hydrolase inhibitors [Biochem. Pharmacol. 38:1061-1067 (1989)], F-C-Ado is a weaker antiviral agent than expected from its Ki value. Nevertheless, the antiviral action of F-C-Ado appears to be targeted at AdoHcy hydrolase. The fact that F-C-Ado is less antivirally active than expected may be due to its further metabolism to its ATP and GTP derivatives. The cytotoxicity of F-C-Ado may be attributed to both its inhibitory effect on AdoHcy hydrolase and the inhibitory effect of its phosphorylated products on host cell RNA synthesis.
Cools
M
M
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Balzarini
J
J
De Clercq
E
E
D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D006710:Homocysteine / Q000494:pharmacology; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D051379:Mice; D009696:Nucleic Acids / Q000096:biosynthesis; D010766:Phosphorylation; D014176:Protein Biosynthesis; D012435:S-Adenosylhomocysteine / Q000032:analysis; D012436:S-Adenosylmethionine / Q000032:analysis
D000998:Antiviral Agents; D009696:Nucleic Acids; D006710:Homocysteine; C069344:6'-fluoroaristeromycin; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000225:Adenine