New weapon in battle against HCMV infection
ANN ARBOR—University of Michigan scientists have developed a potent new drug that has proved highly effective against HCMV generally harmless in individuals with normal immune systems, HCMV attacks AIDS patients and other immunocompromised individuals, including neonates and bone marrow and organ transplant patients. HCMV also has been implicated in dementia in AIDS patients and in some failures of angioplasty.
The new drug, BDCRB—one of a class of compounds called benzimidazole ribonucleosides—is more potent and less toxic than ganciclovir and foscarnet, the two drugs currently used to treat HCMV. Furthermore—unlike ganciclovir—BDCRB has been used safely in combination with the AIDS drug, AZT, in cell culture.
The compound and other members of its class have been licensed by the U-M to Glaxo Wellcome Inc., which is currently conducting pre-clinical studies.
The new compound is described in the Sept. 29 issue of the Journal of Medicinal Chemistry by Leroy B. Townsend, professor of medicinal chemistry in the College of Pharmacy, and John C. Drach, a professor in the School of Dentistry and in medicinal chemistry.
Townsend’s group originally synthesized the lead compound in the class, which was dubbed TCRB, over 20 years ago as a potential anti-cancer agent.
“The initial evaluation of TCRB established that it possessed significant anti-viral activity. A 10-year collaboration with Drach’s laboratory followed, funded by more than $5 million from the National Institutes of Health. The collaboration resulted in the rational design and synthesis of the extremely potent BDCRB,” Townsend explained.
The drug, BDCRB, operates in a unique fashion. ” Most anti- viral agents work by blocking the replication of the virus’s DNA,” said Drach. “BDCRB, however, appears to interfere with the placement of the DNA into a new virus.”
In the process of being assembled, human cytomegalovirus makes a longer piece of DNA than it needs. “We are speculating, but it seems that part of the DNA is wound up like a spool of rope inside the virus while the rest dangles outside through an opening in the wall of the virus,” Drach said.
“Before the virus assembly can be completed and the virus can move on to infect another cell, the dangling portion of the DNA must be clipped off and the opening sealed. Our compound, BDCRB, seems to `jam the clipper’ in some fashion that we do not yet fully understand, so the virus cannot be completed, become infectious and spread.”
“As far as we know, no other anti-viral drug acts by this mechanism,” Townsend added.
In August, Townsend and Drach received a new $2.5 million grant from the National Institute of Allergic and Infectious Diseases, one of the institutes of NIH, to continue their research on BDCRB and other drugs for HCMV infections.
Other researchers currently involved in the development of BDCRB include Karen K. Biron, principal scientist at Glaxo Wellcome, in whose laboratory key discoveries were made that showed the drug acts by blocking the clipping process; and Earl R. Kern, research professor at the University of Alabama, Birmingham, who helped define the drug’s specificity for the human virus.