By David N. Leff
Picture a rope made of twisted fibers of hemp. Two of these strands are in turn coiled around each other, in a double helix, to make a stouter line. Then two of these double helices are again braided together, as the final cable.
This word picture describes, crudely, how DNA molecules form a double helix, which goes on to coil into a second-order helix, which may wrap this supercoiled molecule into a third-order helix, inside the nucleus of a human cell.
It takes a microscope to visualize such a nucleus. If all the genomic DNA in that cell were to be unwound and its strands laid end to end, they would reach roughly the length of a football field.
Every time the cell synthesizes a protein, say, it has to uncoil just the stretch of genomic DNA corresponding to the gene it needs. To perform this unbraiding job, the cell calls up an enzyme called helicase. Its job is to unwind specific regions of DNA or RNA, leading to replication or transcription of the gene's message.
Viral helicase plays a vital role in the replication of the hepatitis C virus (HCV). After it unwinds viral DNA complexes, the resulting strands serve as templates for synthesizing more RNA, or for translation into protein. The new RNA may instead be packaged into newly replicated HCV particles, released from the cells to spread the infection.
In the alphabet soup of viral liver diseases, hepatitis runs from A through G — and still counting. Two of these seven infective viruses, B and C, can be fatal. (See BioWorld Today, April 16, 1997, p. 1.)
Hepatitis C virus causes a chronic, lifelong inflammation of the liver, which may hang in for decades and go on to inflict cirrhosis, liver failure and lethal hepatic carcinoma. An estimated 3.9 million Americans, more than one percent of the population, carry the HCV infection. So do as many Europeans and Japanese.
No vaccine exists yet to prevent the infection; its treatment, interferon-alpha plus an antiviral drug, benefits only a fraction of those who get the therapy.
A logical target for anti-HCV drug design is that helicase enzyme by which the virus replicates. And a logical bullet for hitting that target is a high-resolution map of that enzyme's atomic structure.
X-ray crystallographers at Vertex Pharmaceuticals Inc., of Cambridge, Mass, report this feat in the Jan. 15, 1998, issue of the journal Structure. Their paper's title: "Hepatitis C virus NS3 RNA helicase domain with a bound oligonucleotide: the crystal structure provides insights into the mode of binding."
"This paper," said its lead author, Joseph Kim, "presents for the first time detailed information on the critical interaction between the hepatitis C helicase and viral RNA. Its nucleic acid binding site," he added, "is an attractive target for disrupting this interaction." It and one other site on the helicase, he continued, "are a focus of our ongoing drug design efforts."
Biophysicist Paul Caron, the article's senior author, added, "The structural data we have unveiled also suggest a possible mechanism of nucleic acid unwinding for this and related helicases." *