14 DAY TRIAL // Studies conducted around the world have demonstrated that a double mutant neuraminidase (NA) enzyme called IRHY2 is now enabling the H1N1-2009 version of the flu virus to resist the actions of common vaccines such as Relenza and Tamiflu.
The discovery is very worrying, since this particular strain of the virus caused the first fly pandemic of the 21st century, which killed 18,000 people between April and August, 2009. This represented the second time the H1N1 strain created a pandemic, with the first one being the Spanish flu, in 1918.
The latter was one of the deadliest natural disasters in history. The death toll ranges from 50 to 130 million people, whom the virus killed between January 1918 and December 1920. These figures represent between 3 and 8 percent of the global population at that time.
Now, investigators at the University of Bristol School of Chemistry believe they have learned why the 2009 version of the H1N1 strain is now able to resist antiviral drugs. The research was led by professor Adrian Mulholland and Dr. Christopher Woods.
Working together with Thai scientists, the British group used GPU (graphics processing units) to simulate what goes on inside the virus when it is exposed to the active components of common drugs, such as Relenza and Tamiflu.
The group learned that excessive use of the chemicals has led to significant mutations in the viral NA enzyme, which has now moved from a closed to an open conformation. Tamiflu binds very poorly to open conformations, primarily due to the poor electrostatic charges between the drug and its target.
Details of the new study were published in the May 29 issue of the esteemed journal Biochemistry. The paper argues that the effectiveness of Tamiflu has been reduced 12,374 times, while that of Relenza 21 times. Both treatments are now basically ineffective against the mutated strain.
“Our simulations showed that IRHY became resistant to Tamiflu due to the loss of key hydrogen bonds between the drug and residues in a part of the NA’s structure known as the ‘150-loop’,” Mulholland says.
“This allowed NA to change from a closed to an open conformation. Tamiflu binds weakly with the open conformation due to poor electrostatic interactions between the drug and the active site, thus rendering the drug ineffective,” he concludes.