Computer chips of a type more commonly found in games
consoles have been used by scientists at the University of Bristol
to reveal how the flu virus resists antiflu drugs such as Relenza and Tamiflu.
Professor Adrian
Mulholland and Dr. Christopher Woods from Bristol’s School of Chemistry,
together with colleagues in Thailand, used graphics processing units (GPUs) to
simulate the molecular processes that take place when these drugs are used to
treat the H1N1-2009 strain of influenza—commonly known as swine flu.
Their results,
published in Biochemistry, provide
new insight that could lead to the development of the next generation of
antiviral treatments for flu.
H1N1-2009 is a
new, highly adaptive virus derived from different gene segments of swine,
avian, and human influenza. Within a few months of its appearance in early
2009, the H1N1-2009 strain caused the first flu pandemic of the 21st-century.
The antiviral
drugs Relenza and Tamiflu, which target the neuraminidase (NA) enzyme,
successfully treated the infection but widespread use of these drugs has led to
a series of mutations in NA that reduce the drugs’ effectiveness.
Clinical studies
indicate that the double mutant of swine flu NA known as IRHY2 reduced the
effectiveness of Relenza by 21 times and Tamiflu by 12,374 times—that is, to
the point where it has become an ineffective treatment.
To understand why
the effectiveness of Relenza and Tamiflu is so seriously reduced by the occurrence
of this mutation, the researchers performed long-timescale molecular dynamics
(MD) simulations using GPUs.
Professor
Mulholland said: “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.
“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.”
These findings
suggest that drug resistance could be overcome by increasing hydrogen bond
interactions between NA inhibitors and residues in the 150-loop, with the aim
of maintaining the closed conformation.
