The first study of interactions between a common clinical inhibitor and the HIV-1 protease enzyme has been carried out by an international team with members from the US, Britain and France using neutrons at the Institut Laue-Langevin in Grenoble, France. It provides medical science with the first true picture of how an antiviral drug used to block virus replication actually works, and critically how its performance could be improved.
The findings, reported in the Journal for Medicinal Chemistry, and the neutron techniques demonstrated at the ILL, will provide the basis for the design of a new generation of more effective pharmaceuticals to address issues such as drug resistance. HIV-1 protease is essential in the life-cycle of HIV where it breaks polypeptide chains to create proteins used for replication and producing new infectious virus particles.
Its key role makes it one of the most studied enzymes in the world. For the past 20 years scientists have used highly intense X-rays to investigate the best way to target and block the protease's role in spreading the virus. However, this form of analysis has limitations. The strongest bonds between the enzyme and an inhibitor are usually relatively weak hydrogen bonds, yet hydrogen atoms are virtually invisible to X-ray analysis, leaving scientists to speculate as to how this binding takes place.
To address this uncertainty, scientists from Georgia State University, Purdue University and Oak Ridge National Laboratory in the USA and Harwell Oxford in Great Britain used neutrons at the Institut Laue-Langevin to analyse this binding