Discovery of a new family of inhibitors of human cytomegalovirus (HCMV) based upon lipophilic alkyl furano pyrimidine dideoxy nucleosides: action via a novel non-nucleosidic mechanism.
Following our discovery of the potent anti-varicella zoster virus action of lipophilic alkyl furano pyrimidine 2'-deoxynucleosides, we now report that 2',3'-dideoxy sugar analogues are devoid of anti-VZV activity but are potent and selective inhibitors of human cytomegalovirus (HCMV). The present compounds are active in vitro at ca. 1 microM with cytotoxicity only above 200 microM. Importantly, we have discovered that the new agents do not act as nucleoside analogues, despite their nucleosidic structure, and time of addition studies revealed that the compounds may inhibit HCMV at an event in the replication cycle of the virus that precedes DNA synthesis. They represent new leads in the discovery of improved therapies for HCMV, particularly in view of their novel mechanism of action.
McGuigan
Christopher
C
Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, UK. mcguigan@cardiff.ac.uk
Pathirana
Ranjith N
RN
Snoeck
Robert
R
Andrei
Graciela
G
De Clercq
Erik
E
Balzarini
Jan
J
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects*; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D005663:Furans; D011741:Pyrimidine Nucleosides