Antiviral Activity of 5-substituted Pyrimidine Nucleoside Analogues

From a large series of 5—substituted 1—(2—deoxy——D—ribofuranosyl)—ura— cil (dUrd) , 1—(2—deoxy——D—ribofuranosyl)—cytosine (dCyd) and 1—(—D—arabinofurano— syl)—uracil (araU) analogues that have been evaluated for their antiviral proper— ties, the (E)—5—(2—bromovinyl)derivatives emerged as the most potent and most selec— tive antiherpes agents. (E)—5—(2—Bromovinyl)—dUrd (BVDU) and its congeners, (E)—5— (2—bromovinyl)—dCyd (BVDC) and (E)—5—(2—bromovinyl)—araU (BVaraU) , inhibited the re— plication of herpes simplex virus type I (HSVI) and varicella—zoster virus (VZV) in cell culture at a concentration which was about 5,000— to 50,000—fold lower than the concentration required to affect normal cell growth or metabolism. For example, BVDU inhibited HSV1 replication in primary rabbit kidney cells and VZV in human embryonic lung cells at a concentration of 0.007 pg/ml (0.02 iM) and 0.003 pg/ml (0.01 pM), respectively. A series of sugar—modified analogues and 3'—O— or 5'—O— acyl esters of BVDU have been prepared, and some of these derivatives, i.e. 3'— amino—BVDU and 5'—O—aminoacetyl—BVDU, proved almost as active as BVDU itself. Fur— ther studies revealed that the activity spectrum of BVDU includes, in addition to IISVI and VZV, several other herpesviruses such as pseudorabies virus, bovid herpes— virus type 1, simian varicella virus, herpesvirus saimiri and nuclear polyhedrosis virus. Its antiviral action would depend on a specific phosphorylation by the virus— encoded thymidine kinase, a preferential inhibition of the viral DNA polymerase by the 5'—triphosphate of BVDU (BVDUTP), and, finally, the incorporation of BVDUTP into viral DNA. BVDU has demonstrated high efficacy in several animal model infections, and preliminary clinical studies point to the great promise of BVDU in the topical and systemic (i.e. oral) treatment of HSVI and VZV infections in humans.