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Two research teams have developed compounds with impressive activity against herpes simplex virus (HSV), the cause of oral and genital herpes. The independent achievements come nearly 30 years after the introduction of acyclovir, the only effective drug now available. The compounds are orally active and act on a target that is different from acyclovir's. In animal models, they are more efficacious than acyclovir.

BILS 179 BS, the compound developed by James J. Crute and coworkers at Boehringer Ingelheim R&D centers in the U.S. and Canada, is effective against skin and vaginal lesions in animal models [Nat. Med., 8, 386 (2002)]. One advantage it has over acyclovir is that it can be used less frequently. It is also more effective in cases where treatment has been delayed.

NOVEL New compounds proposed for treatment of herpes, BILS 179 BS and BAY 57-1293, are unlike the drug in current use, acyclovir.

BAY 57-1293, the compound developed by Gerald Kleymann and coworkers at Bayer AG, Pharma Research, in Wuppertal, Germany, hastens the healing of lesions in animal models [Nat. Med., 8, 392 (2002)]. The compound "also blocks viral shedding nearly completely and may help control the further spread of genital herpes in the general population," Kleymann tells C&EN. "We have convincing data that show, for the first time, that recurrence of herpes disease may be prevented if the first episode is treated with BAY 57-1293," he adds.

The new compounds have enormous clinical implications, say Clyde S. Crumpacker and Priscilla A. Schaffer, professors of medicine at Harvard Medical School, in an accompanying commentary. If successfully developed into drugs, "they would represent a major advance in controlling HSV infections," they write.

Both compounds work by acting on two enzymes, helicase and primase, that are part of an enzyme complex HSV needs to untwist
its double-stranded DNA to form single strands and then prime the strands for replication into new viral DNA. By contrast, acyclovir targets DNA polymerase, the enzyme that acts on the primed single strand.

Different lines of evidence indicated that the helicase-primase complex is rate-limiting for HSV replication, according to Crute. Furthermore, the structure of the complex is well characterized, making it a good target for designing inhibitors, Kleymann explains.

Both compounds are more potent than acyclovir, which has limited bioavailability. Its potency is restricted by the fact that it must be phosphorylated by a viral enzyme before it can act on DNA polymerase. As many as one virus per thousand may not have the needed enzyme and thus not be sensitive to acyclovir, Crute notes. The new compounds, by binding to two targets simultaneously, mimic combination therapy with a single drug, Kleymann explains.