Inhibitory activity of S-adenosylhomocysteine hydrolase inhibitors against human cytomegalovirus replication.
Various acyclic and carbocyclic adenosine analogues, which are apparently targeted at the S-adenosylhomocysteine (AdoHcy) hydrolase have been reported to inhibit the replication of a number of pox-, rhabdo-, paramyxo-, arena-, and reoviruses. Here we show that this activity spectrum extends to human cytomegalovirus (HCMV). Of the compounds tested, neplanocin A, 3-deazaneplanocin A, 6'-C-methylneplanocin A and 5'-noraristeromycin were found to be the most potent inhibitors of HCMV replication in vitro. Their 50% inhibitory concentration ranged from 0.05 to 1.35 micrograms/ml. In general, the anti-HCMV activity of the adenosine analogues correlated well with their affinity (Ki) for AdoHcy hydrolase, suggesting that AdoHcy hydrolase may be considered as a target enzyme for anti-HCMV agents. For four compounds (3-deazaneplanocin A, 6'-C-methylneplanocin A (isomers I and II) and 3-deazaadenosine), anti-HCMV potency was greater than could be expected solely from their interaction with AdoHcy hydrolase, suggesting that these compounds may be functioning by an additional mechanism.
Snoeck
R
R
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Andrei
G
G
Neyts
J
J
Schols
D
D
Cools
M
M
Balzarini
J
J
De Clercq
E
E
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D043383:Adenosylhomocysteinase; D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D002586:Cesium; D002712:Chlorides; D003587:Cytomegalovirus / Q000187:drug effects* / Q000502:physiology; D005455:Fluorescent Antibody Technique; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D002712:Chlorides; D002586:Cesium; D006867:Hydrolases; D043383:Adenosylhomocysteinase; C028019:cesium chloride; D000241:Adenosine