Mechanism of antiviral and cytotoxic action of (+/-)-6' beta- fluoroaristeromycin, a potent inhibitor of S-adenosylhomocysteine hydrolase

M Cools, J Balzarini and E De Clercq

Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.

(+/-)-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.

Volume 39, Issue 6, pp. 718-724, 06/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics