THE ANTIVIRAL ACTIVITY OF THE RIBONUCLEOTIDE REDUCTASE INHIBITOR BILD-1351 SE IN COMBINATION WITH ACYCLOVIR AGAINST HSV TYPE-1 IN CELL-CULTURE

BILD 1351 SE is a selective peptidomimetic subunit association inhibit or of the herpes simplex virus (HSV) ribonucleotide reductase (RR) wit h potent antiviral activity both in cell culture assays and animal mod els of HSV disease. The ability of BILD 1351 SE to inhibit the replica tion of HSV-I when used in combination with acyclovir (ACV) for the tr eatment of HSV infections was investigated in baby hamster kidney cell s using a 96-well enzyme-linked immunosorbent assay. The effective con centrations to achieve 50% inhibition (EC50) of virus replication by B ILD 1351 SE in serum-starved and non serum-starved cells were 2+/-0.9 and 4.1+/-1.6 mu M, respectively. The EC50 of ACV under both assay con ditions was equal to 2.7+/-0.9 mu M when tested alone. However, upon a ddition of BILD 1351 SE, the antiviral activity of ACV was potentiated in a synergistic manner as determined by the isobole method. At a con centration of BILD 1351 SE that produced 30% inhibition of HSV-I repli cation, the EC50 of ACV decreased by about 15-fold in confluent cells and 17-fold in serum-starved cells. Similar conclusions were reached w hen evaluating drug interactions by the median dose-effect. Assuming m utually non-exclusive conditions at a drug ratio of ACV/BILD 1351 SE o f 1/2, synergy was demonstrated in confluent cells with a drug enhance ment index at EC50 of 14 and a combination index of 0.25. None of the drug combinations tested showed increased cytotoxicity in comparison w ith each drug alone. These results are consistent with the expected mo de of action of a selective HSV RR inhibitor and support the strategy of combining these inhibitors with ACV for improved therapy of HSV inf ections. (C) 1998 Elsevier Science B.V. All rights reserved.