Author:

Keywords:

Adenosine, Adenosylhomocysteinase, Antiviral Agents, Cells, Cultured, Cesium, Chlorides, Cytomegalovirus, Fluorescent Antibody Technique, Humans, Hydrolases, Molecular Structure, Virus Replication, Science & Technology, Life Sciences & Biomedicine, Pharmacology & Pharmacy, Virology, HUMAN CYTOMEGALOVIRUS, ANTIVIRALS, ADOHCY HYDROLASE INHIBITORS, L-HOMOCYSTEINE HYDROLASE, ADENOSYLMETHIONINE-DEPENDENT METHYLTRANSFERASES, ACQUIRED-IMMUNODEFICIENCY-SYNDROME, HIV-1 REVERSE-TRANSCRIPTASE, SPECTRUM ANTIVIRAL AGENTS, ANTI-DNA VIRUS, NEPLANOCIN-A, L929 CELLS, ADENOSINE-ANALOGS, POTENTIAL INHIBITORS, 0605 Microbiology, 1108 Medical Microbiology, 1115 Pharmacology and Pharmaceutical Sciences, 3107 Microbiology, 3207 Medical microbiology, 3214 Pharmacology and pharmaceutical sciences

Abstract:

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.