April 20, 2000 -- In laboratory studies, an entirely new approach to antiviral drug development is showing remarkable effectiveness against herpes viruses, a large family of viruses associated with many human diseases. In addition, the innovative strategy targets these viruses at such a fundamental level that it may prove useful against a wide array of other viruses. And because the approach attacks viruses indirectly by making the cells they infect profoundly inhospitable to them, the likelihood that viral drug resistance will develop is thought to be extremely low.
University of Pennsylvania Medical Center researchers reported the findings in a study presented today at the Thirteenth International Conference on Antiviral Research in Baltimore, MD.
"This is a novel approach to the development of antiviral drugs," says Luis M. Schang, Ph.D., a postdoctoral fellow and first author on the study. "In the laboratory, we and others are seeing significant viral inhibition with drugs that have no toxicity to cells. If the strategy shows similar success in animals and, eventually, in humans, it should be applicable against many different kinds of viral infections."
Schang emphasizes that a good deal of work remains to be done before the new approach can be validated as a viable treatment for viral infections in humans.
Until now, antiviral drugs have sought to attack viruses directly by interfering with essential proteins produced by the viruses. Scientists have long known, however, that viruses are parasites and depend on the cells they infect for crucial support of their life cycles. Using the herpes simplex virus (HSV) as model target, the Penn team discovered that by inhibiting a particular set of cellular enzymes upon which the virus depends they can successfully block all viral activity while causing the host cells no ill effects.
"To date, all effective anti-viral drugs target viral proteins because the thought has been that knocking out a cellular protein would kill the cell," says Priscilla A. Schaffer, Ph.D., chair of microbiology and senior author on the study. "We've discovered that's not true -- by inhibiting a specific type of cellular enzyme, we've been able to completely block all viral activity without damaging the cells."
The pivotal enzymes are called cyclin-dependent kinases, or cdks. Cells use cdks, along with other proteins, to drive and coordinate cell division. Many viruses, too, rely on cellular cdks for their replication.
The Penn scientists were aware that Laurent Meijer, Ph.D., and his colleagues at the Centre National de la Recherche Scientifique in Roscoff, France, had developed and characterized a variety of cdk-specific inhibitors. With Meijer's assistance, they introduced his inhibitors into HSV-infected cells to test their antiviral theory. What they found was that viral replication ceased while the cells continued to be healthy.
Since the cells depend on cdks for their division but not for many other essential functions, they simply stop dividing in the presence of the drugs. But HSV depends absolutely on cdks for at least three steps in its life cycle, as is likely the case for other viruses, making it vulnerable to cdk inhibitors in multiple ways.
Additionally, the focused reliance of the viruses on cdks, combined with the fact that cdks are cellular, not viral, proteins, strongly suggests that the viruses will have a vanishingly small chance of mutating to develop resistance to cdk inhibitors.
Among the strains of virus completely inactivated by the cdk inhibitors in the Penn experiments were HSV-1 and HSV-2, which chronically infect 80 percent and 20 percent of the world's population respectively and are responsible for painful oral, and genital lesions, themselves a risk factor for sexually transmitted diseases and other health problems. HSV infections can also result in blindness and occasionally in fatal encephalitis.
Thomas Albrecht, Ph.D., and his team at the University of Texas, Galveston, have shown that another herpes virus, human cytomegalovirus, or HCMV, is also inhibited by cdk inhibitors. HCMV chronically infects 80 percent of people worldwide and can be life threatening in immunocompromised individuals such as transplant recipients and cancer patients. Epstein-Barr virus, responsible for infectious mononucleosis, is a virus in the herpes family that the scientists also expect will respond to treatment with cdk inhibitors, although this has yet to be tested.
Indeed, most viruses that replicate in the cell nucleus are potential candidates for the cdk inhibitor antiviral approach, according to the Penn scientists. Thus, members of the adenovirus, papovavirus, and parvovirus families are among the possible targets -- as is HIV.
At least one cdk inhibitor, a drug called flavopiridol, is currently in phase II clinical trials sponsored by the National Cancer Institute as an antitumor agent. Although these trials are investigating a different clinical goal, they have already shown the safety of flavopiridol at doses substantially higher than those thought to be necessary for antiviral treatments. For this reason, data from these trials should facilitate clinical trials of cdk inhibitors as antiviral drugs.
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