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

Abstract:

:(+/-)-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.

journal_name

Mol Pharmacol

journal_title

Molecular pharmacology

authors

Cools M,Balzarini J,De Clercq E

subject

Has Abstract

pub_date

1991-06-01 00:00:00

pages

718-24

issue

6

eissn

0026-895X

issn

1521-0111

journal_volume

39

pub_type

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