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.