Viruses are quite clever, as pathogens go. They are very successful atlying dormant and, when activated, at expropriating cellularmachinery for their own infective purposes. Unlike their bacterialcounterparts, viruses often grow and act by using mechanisms andpathways similar to those of their human hosts. As a result, effectiveantiviral therapeutics are hard to come by.

Even worse, viruses develop resistance to the few drugs available.Their resistance to anti-herpes acyclovir and anti-HIV AZT iscommon, and getting commoner. In fact, resistance to the latter drughas become a critical clinical problem for AIDS patients. Inrecognition of this growing threat to chemotherapy, one of the majorgoals of viral disease researchers is to develop drug candidates thatact on a reaction or pathway that is virus-specific.

This week's issue of Nature, dated Dec. 22, describes a step towarddeveloping antiviral therapeutics. In a paper titled, "A potentpeptidomimetic inhibitor of HSV ribonucleotide reductase withantiviral activity in vivo," Michel Liuzzi and his colleagues at Bio-Mega/Boehringer Ingelheim Research, Inc. in Laval, Quebec reportdesigning a 6-amino-acid peptide inhibitor (BILD 1263) of anenzyme encoded by the herpesvirus genome. These investigatorsfound BILD 1263 to be both potent and viral-specific in its effects.

Defeating Viral Resistance

Their hexapeptide synergizes with acyclovir in a cell-culture herpesreplication assay, and can also affect viral replication in acyclovir-resistant cells. More important, BILD 1263 proved effective in an invivo mouse ocular herpesvirus infection model.

Liuzzi stated that BILD 1263 appears to be the first peptidomimeticinhibitor with in vivo antiviral activity that acts by disrupting anessential protein-protein interaction between two enzyme subunits.

He and his co-authors accomplished their feat by optimizing each ofthe six amino acids in the carboxy terminus of a small subunit ofherpes ribonucleotide reductase. Like other versions of this enzyme,the viral one is formed by the reversible association of two distincthomodimeric subunits.

The carboxy terminus of the small subunit is critical for subunitassociation, and that process can be inhibited by synthetic peptideversions of this portion of the enzyme. By using their peptide designoptimization techniques on the native viral carboxy terminalhexapeptide sequence, Liuzzi's group reported they were able toimprove the potency of their peptide inhibitor "about 200,000-fold."

"We are only at the preclinical level now," Liuzzi told BioWorldToday; "this inhibitor is a prototype. We are working toward thedevelopment of human therapy. The potential combination of BILD1263 with acyclovir is very promising." He is confident that "thedevelopment of a human therapeutic via these techniques would beparticularly useful in light of acyclovir's spreading resistance inherpes-infected individuals."

Don Cohen is a basic researcher in the department of biologicalchemistry and molecular pharmacology at Harvard Medical School.He works in the area of protein-protein interactions, and focuses onrational drug design methods to develop useful candidates fortherapy.

From Micromolar Range To Sub-Nanomolar

Cohen told BioWorld Today that in his opinion Liuzzi's herpesinhibitor "represents an important step forward in the developmentof drugs that target protein-protein interactions." He added, "What isreally exciting is that they have significantly shortened a 9-aminoacid peptide that is effective in the micromolar range, and improvedits potency more than four orders of magnitude so that it is noweffective in the sub-nanomolar range. Now it can enter cells and dosomething."

Cohen said that the ability of BILD 1263 to synergize with acyclovir_ current first-line therapy for herpes infection _ might indicate itsclinical potential. But he cautioned that ribonucleotide reductases arenot essential for viral replication in dividing cells. Although BILD1263 "nicely shows effects in eye disease in mouse, it is not at allclear that what works in mice will work in man," Cohen concluded.n

-- Chester Bisbee Special To BioWorld Today

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

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