Potential new antiviral: why the fanfare?

The news of a new antiviral comes at a Press Conference. That could either mean a blockbuster breakthrough or an unwarranted device to get attention for some otherwise decent but not blockbuster science. Unfortunately, the news that "Experts Identify Compound That May Fight Bird Flu" is of the second type:

Scientists in Hong Kong and the United States have identified a synthetic compound which appears to be able to stop the replication of influenza viruses, including the H5N1 bird flu virus.

The search for such new "inhibitors" has grown more urgent in recent years as drugs, like oseltamivir, have become largely ineffective against certain flu strains, like the H1N1 seasonal flu virus. Experts now question how well and how long the drug would stand up against the H5N1, should it unleash a pandemic.

Researchers in Hong Kong and the Unites States screened some 230,000 compounds that were catalogued with the U.S. National Cancer Institute, and found 20 that could potentially restrict the proliferation of the H5N1.

The experts told a news conference on Wednesday one of the compounds, compound 1 or NSC89853, showed promise.

"We have found a compound that is different from oseltamivir but which acts in the same way," said Leo Poon, a microbiologist at the University of Hong Kong. (Tan Ee Lyn, Reuters)

The paper just appeared in the Journal of Medicinal Chemistry (abstr.; DOI: 10.1021/jm800455g), an American Chemical Society journal. Either their press office or the University of Hong Kong's got this otherwise unremarkable paper on the news wires. So here's the explanation of the science.

The neuraminidase enzyme is the N part of the H/N subtype nomenclature (e.g., H1N1, H3N2, H5N1, etc.). While there are 9 different immunological types of neuraminidase, in terms of viral evolution there seems to be only two main branches of the family tree, group 1 and group 2. Two major antiviral drugs, Tamiflu (oseltamivir) and Relenza (zanamivir) work by blocking the action of neuraminidase. This prevents the virus from successfully budding off an infected cell and thus prevents it from going off to infect other cells. These drugs were designed to inhibit neuraminidase (NA) on the basis of its structure. The design was based on the group 2 neuraminidases (N2 and N9) because their crystal structure was known. Both drugs also worked against group 1 NAs, so it was thought the binding site for both NA groups was similar. Recently, however, the crystal structure for group 1 NA was determined, which includes the N1 NA. It showed that there was a large extra cavity near the pocket that corresponded to the group 2 NA. Using that information, the researchers in Hong Kong, Canada and the US performed a computer simulation screen using data from a US National Cancer Institute database of 230,000 compounds.

This process, which involves a 3-D computer modeling of the lock and key idea, turned up 28 compounds. Some were eliminated because they had undesirable physical properties or were known to be poisonous to cells (cytotoxic). 18 compounds remained. The compound at the top of the list (compound 1, code NSC89853) was the only one capable of inhibiting viral replication, and it did so at roughly the level of oseltamivir (Tamiflu). Moreover it did not compete with oseltamivir in its action. This might have occurred if they were both binding to the same spot on the NA active site, but the two compounds together were additive in their action. Interestingly, compound 1 is a fairly weak NA inhibitor compared to oseltamivir, but it inhibited the virus just as well, suggesting that there might be modes of action independent of NA inhibition.

"Compound 1's" official chemical name is 4-(4-((3-(2-amino-4-hydroxy-6-methyl-5-pyrimidinyl)propyl)amino)phenyl)-1-chloro-3-buten-2-one, which is why it goes under its lab ID name of NSC89853. Maybe someday it will have a trade name, like birdflunivir, but that will be years from now, if ever. Why there was a Press Conference for this paper is beyond me.

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Maybe the reason for the attention is that Tamiflu and Relenza are increasingly inneffective and thus new breakthroughs are critically important

kparcell: Yes, that is the ostensible reason. But even the researchers say that if this pans out (and there are a lot of reasons why it might not), it might be 8 years before it came to market.

Maybe they wanted to attract additional funding to take it to trials/license it out to bigger pharma. Presumably, the press release gets them some publicity. Anyway, most universities seem to have a team that does press releases of papers presented by their research staff. Some get picked randomly from the sciencedaily and eureka alert piles for further distribution in newspapers!

Crawl: This wasn't just a press release. It was a press conference. And there was no biotech company involved, although attracting interest for this might be a motive. More interestingly, the kind of scientific news that bubbles to the surface in the media these days is related to underlying public relations mechanisms as much or more than the importance of the science. Something to keep in mind.

Relenza is NOT increasingly ineffective. The inhaler is as ineffective as it has always been, but that has nothing to do with resistance. In fact, iv zanamivir trials in the 90's WERE effective, but GSK isn't interested in completing expensive trials now,... maybe because in 2013 patents expire and generic zanamivir wouldn't make anyone billions if it was stockpiled, maybe because ignorant statements perpetuate the myth that zanamivir isn't worth further investigation.

"When life gives you a lemon, make lemonade."

The paper and press conference present the latest lemonade recipe.
Add compound NSC89853 to our stockpiled lemon Tamiflu and it is still an important antiviral. During the recent flu season the CDC's lemonade recipe involved rimantadine and Tamiflu (if infection with H1N1 was suspected).

The aim is to maintain the illusion that Tamiflu is still the useful drug it was stockpiled to be.

Miso is correct. I regret I let the statement by a commenter pass without correction.

miso: No, the CDC recommendations are based on data about resistance in H1N1 and H3N2 and make sense. Your poinhts about znamivir are well taken, but these remakrs are silly IMO.

I realise "Miso is correct" appeared to endorse my second post, but your retraction of support by using a straw man was clumsy. I'm sorry you found it silly, perhaps someone can explain it to yuo.

Miso: I'm sorry you found it silly, perhaps someone can explain it to yuo.

Perhaps. You are welcome to give it a try.

My "Miso is correct" response had to do with your comment about zanimivir not showing resistance. The "silly" response had to do with your "lemonade" comment. The comments crossed in the ether.

maybe it's faster than 8 years, when we really need it, e.g. if panflu starts badly.


You are correct in all your statements. For as long as I have been posting on 'effect measure' their has also been a bias against relenza. Both from the scientific community and big business. How long can you beat the drum in the hope it will save lives.!!!

Miso. I salute you for never wavering on zanimivir and trying your best to let the ignorant be enlightened. It will one day save lives for which you can take comfort in.

Also,lets hope, one day soon GSK will be made accountable.