Possible molecular basis for antiviral activity of certain 5-substituted deoxyuridines

Abstract

The antiviral activity of five structurally related pyrimidine nucleosides, E-5-propenyl-2'-deoxyuridine, 5-allyl-2'-deoxyuridine, E-5-(1-butenyl)-2'-deoxyuridine, 54(2-butenyl)-2'-deoxyuridine, and 5-butyl-2'-deoxyuridine, in cell culture against herpes simplex virus type 1 was examined. Analogs in which the C-C double bond of the 5-substituent was in conjugation with the pyrimidine ring were more potent antiviral drugs than were the corresponding nonconjugated and alkylsubstituted analogs. Differences in antiviral activity similar to those observed in cell-culture occurred in virus-infected mice. The molecular basis for the greater antiviral activity of the conjugated isomers was investigated. It was observed that the c6njugated isomer E-5-propenyl-2'-deoxyuridine had a greater affinity for virus thymidine kinase and, as the 5'-triphosphate, for virus DNA polymerase than did the nonconjugated isomer 5-allyl-2'-deoxyuridine. The results are discussed in relation to other data in the literature.Since the discovery of the antiviral activity of 5-iodo-2'-deoxyuridine against herpes simplex virus type 1 (HSV-1), a number of 5-substituted deoxyuridines that inhibit HSV-1 replication have been described. The moieties introduced at C-5 of the pyrimidine ring to confer antiviral activity are diverse (for a review, see reference 9), but of particular interest are the saturated hydrocarbons propyl (5, 12) and ethyl (5, 14), the unsaturated hydrocarbons vinyl (5), allyl (5), and propenyl (8,28), and the halogen-substituted unsaturated hydrocarbons bromovinyl (11) and trifluoropropenyl (8). These compounds differ widely in their ability to inhibit HSV-1, but the reasons for these differences are not clear.Indeed, the development of such compounds has been largely empirical, and their mechanism of action is not fully understood.E-5-(2-Bromovinyl)-2'-deoxyuridine is the most active anti-HSV-1 compound of this type described to date. It can competitively inhibit thymidine phosphorylation (7) by acting as a substrate for HSV-1 thymidine/thymidylate kinase (6, 17). Its 5'-triphosphate has been shown by high-pressure liquid chromatographic analysis to be the most abundant phosphorylated species in the HSV-1-infected cell (27) and to competitively inhibit the utilization of dTTP by virus-induced DNA polymerase (1,25). If other 5-substituted deoxyuridines act by a similar mechanism, differences in antiviral activity in cell culture assays may be related to their respective inhibition constants for thymidine kinase and DNA polymerase. However, the possibility cannot be excluded that other enzymes may be the metabolic target, the inhibition of which results in reduced virus growth.Here we describe the antiherpes activity of two pairs of isomers in which the C-C double bond of the olefinic 5-substituent was conjugated to the double bond of the pyrimidine ring in one of each pair [E-5-propenyl-2'-deoxyuridine (propenyl-dU) and E-5-(1-butenyl)-2'-deoxyuridine (1-butenyl[dU)] and was uncorjugated in the second of each pair of [5-allyl-2...

Comparison of two bromovinyl nucleoside analogs, 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil and E-5-(2-bromovinyl)-2'-deoxyuridine, with acyclovir in inhibition of Epstein-Barr virus replication

“…Furthermore, in studies with acyclic adenosine analogs, substitutions of the 2,3-dihydroxypropyl group in (S)-9-(2,3-dihydroxypropyl)adenine [(S)-DHPA] with 2-phosphonylmethyl derivatives such as in 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and in (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA] greatly enhance antiviral activity (6). Similar structure-activity relation studies on 5-substituted deoxyuridines have been reported (21). Conjugation of the C-C double bond of the olefinic 5-substituent was suspected as a key molecular feature affecting antiviral activity (21).…”

“…Similar structure-activity relation studies on 5-substituted deoxyuridines have been reported (21). Conjugation of the C-C double bond of the olefinic 5-substituent was suspected as a key molecular feature affecting antiviral activity (21).…”

Monoclonal Antibodies to Herpes Simplex Virus Thymidine Kinase

“…O, HSV-1 tk with tk304; II, HSV-1 tk with tkG1Rg; @, HSV-2 tk with tk304. (Sim et al, 1983) -infected cells.…”

Effect of (E)-5-(2-bromovinyl)-2'-deoxyuridine on synthesis of herpes simplex virus type 1-specific polypeptides

“…The biochemical basis for the antiviral activity of BVdU and other nucleoside analogs has been the subject of intense investigation (2,6,20,22; W. H. Prusoff, T. S. Lin, W. R. Mancini, M. J. Otto, S. A. Siegel, and J. J. Lee, in R. T. Walker and E. De Clercq, ed., Targets for the Design of Antiviral Agents, in press). Many of these compounds are incorporated into the viral DNA, resulting in changes in both physical and functional properties of this DNA (1,8,9,14).…”