Scientists Find Two Compounds That Lay The Foundation For
A New Class Of AIDS Drug
A Team of scientists at The Scripps Research Institute has identified two compounds that act on novel binding sites for an enzyme used by the human immunodefiency virus (HIV), the virus that cause AIDS. The discovery lays the foundation for the developments of a new class of anti HIV drugs to enhance existing therapies, treat drug - resistant strains of disease, and slow the evolution of drug - resistanve in the virus. The anti- HIV compounds identified in the new study bind to HIV protease an enzyme essential to the lifecycle of the virus. Drugs that block this viral enzyme are called "protease inhibitors" and currently make up an important part of the successful AIDS drug cocktail known as highly active anti - retroviral therapy (HAART).
Compared with the nine U.S. Food and Drug Administration (FDA)- approved drugs that target HIV protease, however, the two new componds, which are small chemical units or "fragments," bind with two novel parts of the molecule. This could make future drugs incorporating the fragments' novel structural elements a useful complement to existing treatments.
"The study's results open the door to a whole new approach to drug desig against HIV protease," said Scripps Research Associate Professor C. David Stout, senior author of the study. "The fragments bound at not one, but two, different cervices in protease outside the active site. This is an important proof -of-concept that the protease molecule has two non-active site binding pockets ('allosteric sites') which can now be exploitd as a powerful new strategy to combat drug- resistance in HIV."
Research Associate Alex L. Perryman, first author of the paper and member of Professor Arthur Olson's laboratory at Scripps Research, added, "The experiments validate my hypothesis developed from computational modeling that HIV protease has pockets on its surface besides the active site that can bind drugs. Drugs developed to target these sites could be used to make current FDA- approved active site inhibitors more potent and to restore their effectiveness against drug- resistant superbugs. The whole strategy of targetting non-active sites may also prove useful against other disease, especially when there are mutations that cause drug resistance."
The Long Arm of HIV Protease
Approximately 33 million people are currently living with HIV infections, 2.7 million of whom were newly infected in 2008, according to the most recent statistics available from the World Health Organization. While HAART therapy has prolonged survival and improved the quality of life for many AIDS pateints, a rapidly growing portion of new HIV infections involve drug- resistant strains.
Perrymn has been interested in the problem of drug resistance for some time. As a Howard Hughes Medical Institute (HHMI) pre-doctoral fellow in the laboratory of HHMI Professor J. Andrew McCammon at the University of California, San Diego, Perryman conducted extensive computer simulations of a drug-resistant HIV protease molecule and campared them with a normal HIV protease molecule. This theoretical effort laid the groundwork for the current experimental study.
As is often the case in biology, the shape of the HIV protease reflects and dictates its function. In the process of reproducing itself, the virus makes long protein chains, which the protease splits into shorter pieces to enabel the final assembly of new HIV virions. To split off the pieces from the longer chain, the protease has two scissor-like flaps on each side of the molecule. The flaps open to let in the viral protein chain, which threads itself into the flaps then close, crossing in the middle over a binding pocket and cleaving the protein chain into smaller pieces.
Current HIV-protease drugs mimic the shape of certain regions of the HIV protein chain (i.e., the "cleavage sites") and bind to the active site in the hollow center of protease. Once this site is blocked by the drug, the protease is disabled, and HIV cannot make new infectious particles. Thus, protease drugs impede the spread of the HIV infection to other cells within a patients.
Perryman wanted to find out what was different about drug-resistant strains of the virus information that was not obvious from static pictures of the molecules. So, he conducted computer simulations of the movement of a particularly nasty multi-drug-resistant mutant strain of HIV (V82F/I84V).
The findings showed that the flaps of the drug-resistant protease molecule tended to be open more often than their standard counterparts, and they were also more flexible. While the anti-HIV drugs still fit into the active site binding pocket, more energy was needed to close the flaps than the drugs could muster. As a consequence, the drugs wouldn't stay in the pocket remained available for the HIV protein chain, which was still able to create new infectious particles.
In their simulation, Perryman and his colleagues identified a potential solution to this problem. Like restraining the handle-end of a pair of scissors to keep the blades from opening too wide, a new type of drug might be able to bind to alternate sites on the sides of protease, restraining the flaps from their ends and proving the current anti-HIV drugs enough help to close the flaps and disable the protease. Instead of blocking the protease's active site, these componds would be "allosteric fragments," small molecule building blocks that shift the dynamics of molecule so it prefers a different conformation (shape).
The plan sounded good in theory, but could it work in practice?
(The research will appear as the cover story of the March issue of the Journal Chemical Biology & Drug Design.)
Posts
No comments:
Post a Comment