Viruses survive by being camouflaged. They redirect much of thehuman host cell's efforts toward fulfilling their need to replicate andgrow. Since they use the host's metabolic machinery and pathways todo this, they can remain undercover. In this complex game of hide-and-seek, effective antiviral agents are hard to develop.

And often viruses lie dormant in the genome for years beforewreaking havoc on their host. When they are reactivated, virusesquickly multiply and then conquer. Even successful viraltherapeutics, like acyclovir, can be overwhelmed because the highrate of viral replication allows development of resistant strains. As aresult, viral researchers are looking for antiviral drug candidates thataffect a virus-specific pathway.

In the Feb. 27 Proceedings of the National Academy of Sciences(PNAS) a promising strategy for developing potential antiviral drugcandidates is described. In an article entitled, "Specific inhibition ofherpes simplex virus DNA polymerase by helical peptidescorresponding to the subunit interface," Paul Digard and colleagues,of Harvard Medical School and the Joslin Diabetes Center in Boston,and SmithKline Beecham plc, in Philadelphia, report on theirdevelopment of a 36-amino acid peptide inhibitor of herpes DNApolymerase.

As stated in the article, the herpes simplex virus DNA polymeraseconsists of a catalytic and an accessory subunit. Mutations affectingthe extreme C-terminal end of the catalytic subunit eliminate viralreplication. Such mutations apparently affect interactions of the twosubunits that are critical for herpes DNA polymerase activity.

These investigators have developed a 36-amino acid peptide inhibitorthat corresponds to the C-terminal region of the catalytic subunit ofherpes DNA polymerase. It inhibits polymerase activity byinterfering with the association of the two subunits. They were able toreduce the size of an effective inhibitor to a peptide containing themost C-terminal 18 amino acids of the polymerase.

Exploiting Differences Between Virus And Host

As Donald Coen, molecular virologist and senior author of the PNASarticle, told BioWorld Today, "We were interested in this problemfor two reasons. First, there was the potential for the development ofinhibitors that affect protein-protein interactions for herpes and otherviruses. Second, at the basic science level, it provided a chance tostudy the mechanisms of how proteins interact.

"Present antivirals, like acyclovir, also target DNA polymerase,"Coen said, "and they exploit rather subtle differences between thehost and viral enzymes. With inhibitors of protein-protein interaction,we could affect regions of the polymerase for which no homologicshave been detected in host polymerases." When BioWorld Todayasked Coen about the development of viral resistance to inhibitors ofprotein-protein interaction, he said, "Resistance to these inhibitorsprobably will still develop. Only time will tell if the frequency of itsdevelopment is less than the two established drugs."

At present, Coen said that, "Everything is still in a test tube. We havedone this work in collaboration with Preston Hensley at SmithKlineBeecham. We are continuing this collaboration."

Michael Cordingly, who is the Director of Biochemistry atBioMega/Boehringer Ingelheim Research Inc., in Laval, Quebec, said"This is a great example of how molecular biology can be of use inbeginning the search for lead structures for therapeutic development.Coen and his colleagues have successfully illustrated the concept ofusing an inhibitor of DNA polymerase as an antiviral agent.

"However, showing binding is different from being at the verge oftherapeutic development," he said. "They are still a few steps awayfrom a lead structure. The type of effort needed will be a reduction inthe number of amino acid residues or the development of an analogstructure that has the same effect. And the binding characteristics willstill need to be optimized by working with the structure."

Cordingly explained that, "Peptides are still relatively poortherapeutics. With each candidate therapeutic developed, one has toshow that it will penetrate cells in culture. Then a strategy forpractical large-scale production must be put in place. Finally, clinicaltrials must show that the peptide can be delivered effectively." In theend, the development of peptide therapeutics remains a long, arduoustask. n

-- Chester Bisbee Special To BioWorld Today

(c) 1997 American Health Consultants. All rights reserved.

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