Antiviral Activity of Nucleoside Analogues: The BVDU Connection

Abstract

(E)-5-(2-bromovinyl)-2’-deoxyuridine (BVDU, Brivudin) is a highly potent and selective inhibitor of herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) infections. This chapter provides an update on the activity spectrum, mechanism of action, and other unique properties that is shared by BVDU and its congeners, and those are all determined by the presence of the (E)-2-bromovinyl entity. The high selectivity of BVDU toward HSV-1 and VZV depends primarily on a specific phosphorylation of BVDU to its 5'-diphosphate by the virus-encoded thymidine kinase (TK). After further phosphorylation by cellular enzymes to the 5'-triphosphate, the compound interferes as a competitive inhibitor/alternate substrate with the viral DNA polymerase. The specific phosphorylation by the HSV- and VZV-induced TK also explains the marked cytostatic activity of BVDU against tumor cells that have been transduced by the viral TK genes. BVDU or its analogs are degraded by thymidine phosphorylase to (E)-5-(2-bromovinyl)uracil (BVU), they may potentiate the anticancer potency, as well as toxicity, of 5-fluorouracil. This ensues from the direct inactivating effect of BVU on dihydropyrimidine dehydrogenase, the enzyme that initiates the degradative pathway of 5-fluorouracil. BVU substitute is the prime determinant in the unique behavior of BVDU, which, therefore, can be considered as the pharmacophore of the molecule.