A number of structurally related 5-substituted pyrimidine 2'-deoxyribonucleosides were synthesized and tested for antiviral activity against herpes simplex virus type 1 (HSV-1) in cell culture. A minimum inhibitory concentration was determined for each compound, and from a comparison of these values a number of conclusions were drawn with regard to those molecular features that enhance or reduce antiviral activity. Optimum inhibition of HSV-1 in cell culture occurred when the 5-substituent was unsaturated and conjugated with the pyrimidine ring, was not longer than four carbon atoms in length, had E stereochemistry, and included a hydrophobic, electronegative function but did not contain a branching point. Such features are contained in (E)-5-(2-bromovinyl)-2'-deoxyuridine, which was the most active of the compounds described.

In isolation human plasminogen possesses no enzymatic activity, yet upon formation of an equimolar complex with the bacterial protein streptokinase, it acquires a plasminogen activator function. The region(s) of plasminogen and of streptokinase which mediate complex formation has (have) not been previously published. Here it is reported that a single-residue substitution (Arg719-->Glu) in the serine protease domain of full-length Glu-plasminogen substantially reduces its affinity for streptokinase. The plasminogen variant displays no other significant differences from the wild-type molecule with respect to activation by two-chain urokinase-type plasminogen activator, recognition by monoclonal antibodies, or ability to undergo conformational change. It is concluded that Arg719 in human plasminogen is an important determinant of the streptokinase binding site, although further sites are likely to contribute both to the affinity of plasminogen for streptokinase and to mechanisms by which the active site is formed within the complex.

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...

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