Over two millennia ago, a Greek philosopher, Heraclitus by name (c.540 - c. 480 B.C.), foretold why it is so difficult to create a vaccineagainst the AIDS virus or hepatitis C infection. He wrote: "You couldnot step twice into the same river; for other waters are ever flowingon to you."

Joshua Boger, president and CEO of Vertex Pharmaceuticals Inc. inCambridge, Mass., cites this ancient epigram as authority for hisdictum: "There's no reasonable prospect in my opinion for a vaccinefor hepatitis C virus."

On the other hand, Boger said he sees every prospect for an antiviraldrug against hepatitis C infection. So does Peter Johnson, presidentand CEO of Agouron Pharmaceuticals Inc., of San Diego.

Both their companies reported independently in today's Cell that theyhave mapped the 3-D crystal structure of the principal hepatitis Cvirus (HCV) protease, without which enzyme it can't reproduce.

Boger is bearish on the outlook for a vaccine against HCV, he toldBioWorld Today, "because unlike hepatitis A and B, C is a multiple-multiple poly-strain virus. It mutates rather rapidly as well, so it'smuch more of an HIV-type story. Although unrelated to HIV, itreproduces in a very similar fashion; it has the same low-fidelity ofreproduction, which translates into a high ability to mutate."

He added: "It's the Heraclitus problem: You can't catch the hepatitisC virus looking the same externally twice."

Agouron's Johnson said he thinks that "there are prospects for ahepatitis C vaccine, considering that some of the other hepatitisviruses are amenable to that approach." But he added, "a HCVvaccine would be scientifically unrelated to this discovery of HCV'scrystal structure."

The Vertex paper in Cell bears the title: "Crystal structure of thehepatitis C virus NS3 protease domain complexed with a syntheticNS4A cofactor peptide." It follows immediately after Agouron'sarticle: "The crystal structure of the hepatitis C virus NS3 proteasereveals a trypsin-like fold and a structural zinc binding site."

Boger explained why "You can't get functional proteins in amammalian cell without this viral enzyme.

"What the protease does," he said, "is make one long protein, whichhas to be cut into its structural and non-structural segments. Thestructural proteins, used physically to build another virus, are cut byhuman cell enzymes. The non-structural protein, namely the one thatHCV needs to assemble itself and replicate, is cut in four places outof five by the HCV protease. If that protease doesn't make those cuts,the virus can't reproduce."

HIV Protease, Paradigm For HCV Enzyme

Protein structural analysis of the human immunodeficiency virus ledAgouron and two other pharmaceutical companies to develop theirHIV protease-blocking drugs, now on the AIDS market.

Vertex, with its collaborator, Glaxo-Wellcome plc, of London, has itsanti-AIDS protease blocker in Phase II clinical trials, in the U.S. andEurope. (See BioWorld Today, Sept. 16, 1996, p. 1.) "We plan tobegin pivotal trials with that compound," Boger said, "by the end ofthis year, 1996, with an eye to market introduction in 1998."

What makes their version anything more than a "me-too" drug,compared with the three anti-HIV protease-blockers alreadyapproved?

"A very good question," Boger said, "and very dear to Glaxo's heart.They've put it at the very top of their development pipeline." Thethree already on the market, he explained, have food-relatedproblems of patient compliance.

One must be taken thrice daily on an empty stomach, another just asoften on a full stomach, the third three times a day after a high-fatmeal. "That one sounds great to McDonald's fans," Boger observed,"but it's hard for real people to comply with.

"We don't have any of these food effects in our twice-a-day product,"he said, "And it's more potent than any of the three marketed ones."

How soon will the Vertex hepatitis C antiprotease be ready forpivotal trials?

"I'll know for sure the day before," Boger replied. "Projecting time-lines in this business is not a good way to make a living.

"What we can say," he allowed, "is that historically, on the basis ofour HIV experience, the time from when we started the structuralanalysis program to when we had a compound going into clinicaldevelopment is about three years. Perhaps we can be faster withHCV, but that's no promise."

So far, since Vertex completed its structural analysis early thissummer, "We've been doing drug design based on that 3-D road mapfor quite a while now. We have a number of potent protease-inhibiting lead compounds, but no drug or clinical candidates as yet."

Agouron is at a similar stage of structure-prompted anti-hepatitis-Cdrug design. "What I think is important here," Johnson toldBioWorld Today, "is that there is a new line of attack on pathogenicviruses generally. Before the proteases, pretty much all antiviraldrugs operated as nucleoside analogues. Where HIV proteases led theway, there are now four viral pathogens, which can be attacked in thesame way."

In 1994, Agouron solved the 3-D protease structure of the commoncold rhinovirus, and last month did as much for the cytomegalovirusprotease. So did three other companies. (See BioWorld Today, Sept.25, 1996, p. 1). "We published in Cell, and three other groups inNature, all on the same day," Johnson observed. "It's sort of aremarkable coincidence when it's so close, but it does happen."

That's what happened when Agouron and Vertex published theirHCV protease structures in today's Cell. "It was just coincidence thatthey submitted simultaneously," a Cell editorial spokesman toldBioWorld Today.

Until 1989, hepatitis C was known as "non-A, non-B hepatitis." Thatwas the year that Michael Houghton at Chiron Corp. cloned themaverick pathogen, and gave it a letter of the alphabet all its own.

Now HCV has a dire reputation all its own. Chronic HCV infection isa global disease, affecting one percent of the planet's people, andwith an estimated 300 million carriers. It's the leading cause of livercancer in the U.S. as well as in China.

In Japan, about 4 million people, 5 percent of the population, arechronically infected. In the U.S., the Centers for Disease Control andPrevention in Atlanta, puts the number at 3.9 million, nearly 2percent of all Americans.

Boger cites "the weight of the evidence, and views of people in thefield, to the effect that those with chronic infection are just in earlystages of the disease." It can persist for decades, and progress tocirrhosis and carcinoma of the liver. With no vaccine in sight, theonly treatment is alpha-interferon, which has nasty side effects andlimited therapeutic efficacy. n

-- David N. Leff Science Editor

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

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