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25 amino acids against avian influenza

Only the quickest can keep up in this race. Although avian influenza inhibitors such as Tamiflu or Relenza have only been on the market for a few years, experts have already observed the first viral strains that are resistant to these compounds. The danger of a pandemic is actually quite real; the avian influenza pathogen could, at any time, evolve into a dangerous human pathogen. About a year ago, Prof. Dr. Martin Schwemmle and his team in the Department of Virology at the University Hospital of Freiburg, discovered a completely new starting point in the fight against these dangerous viruses. In the meantime, the scientists are working together with the Zurich-based company Pike Pharma to develop a compound that might be effective over longer periods of time.

The influenza A genotype H5N1 is predominantly found in birds and is very aggressive. However, over the last few years, H5N1 infections have also occurred in humans and have led to the death of more of 50% of people infected. One of the reasons why a pandemic has, thus far, been prevented, is the fact that the avian influenza virus does not easily spread from human to human. The respiratory epithelial cells of the lung are the primary targets of the avian influenza virus. The viruses become included into respiratory secretions and only spread by small-particle aerosols generated during sneezing, coughing and speaking, not during normal breathing. “At present, this shortcoming still protects us from a catastrophe that might be as damaging as the Spanish Flu which led to a global disaster in 1918,” said Prof. Dr. Martin Schwemmle from the Department of Virology at the Institute of Medical Microbiology and Hygiene at the Freiburg University Hospital. “However, this might change soon. Viruses are able to adapt rapidly to new hosts.”

Weak points are disappearing

Viruses have two possibilities to improve their prospects of successful infection: The enzyme RNA polymerase, which replicates the viral genome in the host cells, introduces mistakes that lead to genetic variations and hence to new viral properties. Secondly, the viruses can also exchange entire gene segments with other viruses, thereby transferring viral properties to each other. In the case of avian influenza, the only thing required for H5N1 infections to become a pandemic threat is for a host to be infected that can carry both the H5N1 virus and viruses that can easily be transmitted between humans. Domestic pigs are such hosts and humans are traditionally in close contact with pigs. If the genomes of two suitable viral strains mix in the pig, then humans might soon become infected with the new viruses and spread them.
“Nobody knows when a pandemic will break out,” said Schwemmle. “However, the population should be prepared.” Apart from plans involving mainly infrastructural aspects associated with a pandemic, for example, the availability of hospital beds, pandemic plans also cover the availability of drugs that prevent avian influenza infections. But inhibitors such as Tamiflu or Relenza are at risk of becoming ineffective against future viral strains as some flu strains have already developed resistance to these compounds. The example of Tamiflu clearly highlights the problem that is often experienced with viral inhibitors: the drug blocks the enzymatic activity of neuraminidase, a viral protein, and prevents virus particles from detaching from the receptors on the host cells. This prevents the virus from leaving the infected cells and hence from spreading in the body. However, the enzyme is prone to genetic mutations, then the structures the drug is targeting will disappear and the drug becomes ineffective. Therefore, a compound that targets viral regions that are less prone to mutations would be far more effective.
Schematische Darstellung eines Experiments, mit dem sich die antivirale Wirkung von Substanzen feststellen lässt. Zunächst werden humane Zellen mit Influenza A Virus infiziert, nach einer Stunde wird das antiviral aktive Peptid zugegeben. Nach weiteren 24 Stunden werden die infektiösen Viruspartikel im Überstand der Zellen mittels des Plaque Assays bestimmt.
Schematic of an experiment showing the antiviral effect of certain substances (e.g., short protein fragments (peptides)). (Figure: Prof. Dr. Martin Schwemmle)

New starting point

In this plaque test, a peptide with a length of 25 amino acids was tested for its antiviral effect. In the absence of the peptide, the virus succeeded in infecting and destroying far more cells (left). The infected cells were unable to take up the blue dye. (Photo: Prof. Dr. Martin Schwemmle)
Schwemmle and his team of researchers identified such a region about one year ago. This region is located on the viral RNA polymerase enzyme that is necessary for the synthesis of viral RNA. This region is comprised of only 25 amino acids and links two of the enzyme’s three subunits with each other. If this 25-amino acid stretch is removed from the polymerase subunit to which it belongs and introduced into human cells, then influenza viruses are unable to replicate in these cells. “The peptide binds specifically to the protein-protein interaction domains in the subunits responsible for complex formation, thereby interfering with polymerase complex assembly and hence preventing viral replication,” explains Schwemmle. The protein fragment is highly conserved, which means that it is the same in at least 95 per cent of all influenza A strains. This suggests that viruses are barely able to survive with a mutation in this particular sequence stretch. If a drug were able to target this region, then influenza viruses might possibly be unable to adapt so easily to new hosts.

“We are now looking for substances that behave like the short protein fragment and that provide a new strategy for developing antiviral compounds,” said Schwemmle, who is currently working with his team and the company Pike Pharma from Zurich on developing such compounds. The work is still in its infancy, as the researchers have to test between 100,000 to 300,000 substances. They are using expensive robots to pursue their goal. Once a suitable substance is found, initial tests will be carried out on mice. It is hoped that a promising compound will be found and subsequently be tested in clinical trials. “We have a lot of work ahead of us and the path to an effective drug is long though very exciting,” said Schwemmle.

mn – 23 July 2008
© BIOPRO Baden-Württemberg GmbH
Further information:
Prof. Dr. Martin Schwemmle
Department of Virology
University Hospital Freiburg
Hermann-Herder-Straße 11
79104 Freiburg
Tel.: +49-(0)761/203-6526
Fax: +49-(0)761/203-6562 oder -6639
E-mail: martin.schwemmle@uniklinik-freiburg.de
Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/25-amino-acids-against-avian-influenza