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Volume 91 Issue 8 | p. 7 | News of The Week
Issue Date: February 25, 2013 | Web Date: February 21, 2013

Neuraminidase Inhibitors May Work When Tamiflu Doesn't

Drug Discovery: Agents block flu by a covalent mechanism, which could help prevent virus from becoming resistant
Department: Science & Technology | Collection: Life Sciences
News Channels: Biological SCENE
Keywords: flu, virus, neuraminidase, drug resistance, Tamiflu
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Virus (blue sphere) adheres to sialic acids (green) on host cell surface (red). Inhibitors (yellow) block active site of neuraminidase (blue appendages), preventing the enzyme from cleaving sialic acid to let the virus spread.
Credit: CSIRO
Graphic shows that when a new virus (blue sphere) is produced in a host cell (red), it initially adheres to the producing-cell surface by binding to sialic acid receptors (green pegs) located there. The virus can spread to other host cells only when viral-surface neuraminidase enzyme (large blue appendages) cleaves the host cell-surface sialic acids. The new inhibitor (yellow), which resembles sialic acid structurally, plugs up the neuraminidases, preventing them from freeing the virus and providing sufficient opportunity for the immune system to remove the virus.
 
Virus (blue sphere) adheres to sialic acids (green) on host cell surface (red). Inhibitors (yellow) block active site of neuraminidase (blue appendages), preventing the enzyme from cleaving sialic acid to let the virus spread.
Credit: CSIRO
[+]Enlarge
Neuraminidase’s native substrate, sialic acid (top), is structurally similar to new mechanism-based flu enzyme inhibitors (such as the one shown, bottom).
Structures show how an example of a mechanism-based inhibitor (bottom) is structurally similar to neuramindase’s native substrate, sialic acid (top).
 
Neuraminidase’s native substrate, sialic acid (top), is structurally similar to new mechanism-based flu enzyme inhibitors (such as the one shown, bottom).

The rise of influenza strains resistant to current flu treatments has drug developers looking for new leads. Hope could come from a new family of inhibitors that may effectively block the flu virus from spreading in the body and thwart its tendency to become drug-resistant.

The new agents, devised by a University of British Columbia-based team, inhibit the flu virus enzyme neuraminidase. They halt the spread of flu viruses in cell culture and animal tests, including strains resistant to the commercial flu drug Tamiflu, which also inhibits neuraminidase. The compounds could therefore lead to a Tamiflu backup drug.

Flu afflicts millions worldwide each year, causing debilitating symptoms and hundreds of thousands of deaths. When the virus infects people, it enters airway cells and replicates. Progeny emerge as buds attached to sialic acids on cell surfaces. If neuraminidase cleaves these acids, the viruses are released to infect more cells. Inhibitors turn off this activity, blocking proliferation.

Four neuraminidase inhibitors are approved or in development for postinfection treatment. Tamiflu is the most popular, but flu can evolve into strains insensitive to it. Relenza is administered by oral inhalation, which has limited its use. Peramivir was withdrawn from a Phase III trial last year, and laninamivir is scheduled to enter Phase II, although both are approved in Asia.

The new compounds emerged from efforts by Stephen G. Withers and coworkers to determine how neuraminidase works molecularly (Science, DOI: 10.1126/science.1232552). Their study shows that neuraminidase catalyzes sialic acid cleavage by a mechanism involving a covalent intermediate. They determined the structure of the intermediate and designed sialic acid analogs that bond covalently to the viral neuraminidase active site but release very slowly, thus disabling it, and do not inhibit human neuraminidase. The compounds may evade viral resistance more effectively than Tamiflu because their structures more closely resemble that of sialic acid. Also, covalent bonding permanently inactivates the neuraminidase active site; Tamiflu and the three other inhibitors bind noncovalently.

The Centre for Drug Research & Development, in Vancouver, is seeking private-sector partners and investors to help develop the new inhibitors commercially.

Drug-resistant viruses that cause pandemics “could be devastating for lack of any means to limit their spread or pathology,” comments chemical glycobiologist James C. Paulson of Scripps Research Institute, in California. The new inhibitors “should be developed as drugs for human testing that could be stockpiled or serve as alternatives.”

Relenza discoverer Mark von Itzstein of Griffith University, in Australia, says the new data “provide valuable insight into possible next-generation influenza drugs.”

Flu expert Larisa V. Gubareva of the Centers for Disease Control & Prevention, in Atlanta, is more cautious, saying that discovery of the covalent mechanism is noteworthy but the new inhibitors’ efficacy and advantages over existing inhibitors have yet to be fully evaluated.

COMBATTING FLU DRUG RESISTANCE
Animation shows the infective life cycle of flu virus and how it can be interrupted by one of the new mechanism-based inhibitors. Flu virus (blue sphere) first infects a host cell (red). It proliferates inside the cell. Progeny then bud to the cell surface, where they attach to sialic acid receptors (green). An enzyme called neuraminidase (blue appendages) on the surface of the virus can cleave these sialic acid links, releasing the virus and allowing it to spread to other cells. Or the sialic acid-linked virus can be trapped on the surface by mechanism-based inhibitors (yellow) that block neuraminidase, giving immune-system cells (gray) time to clear the virus from the system.
Credit: CSIRO
 
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