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BIRMINGHAM, Alabama – Molecular virologist Chad Petit, Ph.D., uses basic science to fight the flu through atomic experiments.
This includes a deadly bird flu virus in China called the H7N9 bird flu virus. Since 2013, 1,725 people have been infected with the H7N9 virus, including 623 deaths. Even if they are not very contagious for humans, only three mutations could change this situation.
As part of research to improve treatments for influenza H7N9 and other influenza strains, Petit and colleagues at the University of Alabama in Birmingham detailed the binding site and mechanism of inhibition of two inhibitors experimental small influenza viruses. Their report is published in Biochemistry Journal,
The two experimental inhibitors studied by Petit, an badistant professor of biochemistry and molecular genetics at UAB, are small molecules whose precise mechanism of action was unknown. Inhibitors target the function of a key protein called NS1 influenza, which plays several roles to block the body's immune response during an influenza infection. Thus, NS1 is essential for the survival and adaptability of the influenza virus.
Petit and his colleagues used nuclear magnetic resonance spectroscopy (NMR) to probe inhibitor interactions with NS1. They first showed that the inhibitors – called A9 and A22 – interacted with only one of the two independently folded domains of NS1, the NS1 effector domain.
The researchers noted that the structures of the two small molecule inhibitors were very similar to a fragment of a host protein called CPSF30 that the NS1 effector domain binds to bypbad the body's immune response. Therefore, the researchers hypothesized that A9 and A22 block viral replication of influenza and block NS1 function by interfering with the interaction between effector domain NS1 and CPSF30.
NMR data revealed the particular amino acids of the effector domain NS1 that are involved in the binding of the inhibitor. Researchers – using two NS1 proteins significantly different from separate influenza strains, including the H7N9 strain – showed that similar amino acid sequences in both NS1 proteins were involved in inhibitor binding.
The NS1 protein of the "Spanish" virus of 1918
In addition to the Chinese H7N9 NS1, the other NS1 protein tested was the NS1 effector domain of the "Spanish" flu of 1918, which infected a third of the world's population a century ago and killed between 50 and 100 million people.
UAB researchers then used X-ray crystallography, led by Assistant Professor Todd Green, who holds the Microbiology Chair in Microbiology, to determine the three-dimensional structure of the NS1 effector domain of "Spanish" flu. from 1918. This allowed them to map the A9 / A22 binding site to this structure, which confirmed their hypothesis – A9 and A22 interact with the hydrophobic pocket of the NS1 effector domain which is known to bind to the host protein CPSF30 .
The crystallographic data also showed that the NS1 effector domain is able to dimerize using an interface different from two other known dimers of the NS1 effector domain. The biological significance of this new form of dimer is unknown.
"Overall, our findings provide strong evidence for the mechanism of action of two anti-influenza compounds that target NS1, and provide important structural information on NS1 that we hope will promote and inform development and optimizing flu treatments based on A9 and A22, "said Petit.
The need for new antiviral compounds is great. Each year, influenza strains kill between 250,000 and 500,000 people worldwide, and the virus is characterized by rapid changes to produce pandemic strains that are immune to few people. Viral resistance has limited the effectiveness of several antiviral compounds previously developed to treat influenza.
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