New details of the way an anti-HIV drug blocks replication of the virus, revealed in a Georgia State University study, will allow researchers to design more effective drugs to fight the disease HIV/AIDS, including drug-resistant strains.
To understand the impact of the research led by Professor Irene Weber, it’s important to know that anti-HIV drugs are designed at the molecular level. Scientists start by mapping out the structure of the proteins produced by the virus itself. Once they understand that, they can design drug molecules that bind on to the target virus protein and interfere with its ability to reproduce.
Weber, a professor of biology and of chemistry, and her group studied a particular enzyme, called HIV-1 protease. This enzyme plays a key role in the reproductive mechanisms of HIV. Many existing medications are aimed at this enzyme, binding to it so it can’t do its reproductive job.
Until now, scientists have used highly intense X-rays to study the structure of the enzyme. The problem with this method is that hydrogen atoms are a key part of the enzyme’s functioning, but hydrogen atoms are also almost invisible to X-rays.
Weber and her team used a different technology, using beams of neutrons that could clearly show the position of hydrogen atoms within the enzyme. They looked specifically at a drug called Amprenavir, which was first approved for the treatment of HIV/AIDS in 1999.
What they found went against earlier understandings of how the drug and the enzyme interacted. Once the researchers could see the hydrogen atoms, they could also see that hydrogen bonds were much less important to the functioning of the drug than anyone had previously thought.
The study presents drug designers with a whole new set of sites where drugs can potentially bind to the enzyme. If these designs work out, it could mean a new generation of drugs that work better at lower dosages.
“This neutron crystal structure provides important new insights into the chemistry of how drugs bind HIV protease,” Weber said.
The study was funded through several National Institutes of Health grants, and included scientists from the U.S., Great Britain and France using the LADI-III neutron diffractometer at the Institut Laue-Langevin in Grenoble, France.
These findings were published in the June 28 issue of the Journal of Medical Chemistry. The full citation: Weber, I.T., Waltman, M.J., Mustyakimov, M., Blakeley, M.P., Keen, D.A., Ghosh, A.K., Langan, P., Kovalevsky, A.Y. Joint X-ray/neutron crystallographic study of HIV-1 protease with clinical inhibitor amprenavir – insights for drug design. (2013) J. Med. Chem. 28 June.