New Drug-Screening Method Yields Long-Sought Anti-HIV Compounds
The Drug Candidates Act on a Target Unlikely to Mutate
LA JOLLA, CA - June 13, 2012 - Scientists at The Scripps Research Institute have used a powerful new
chemical-screening method to find compounds that inhibit the activity of human immunodeficiency virus (HIV), the virus that causes
AIDS. Unlike existing anti-HIV drugs, the compounds bind to a protein called "nucelocapsid," which is unlikely to mutate into
drug-resistant forms.
 "Most of the nucleocapsid-inhibiting compounds that have been identified to date are very toxic, but our screening method
identified inhibitors that are less toxic and thus more likely to lead to useful drugs," said Scripps Research Associate Professor Bruce
Torbett. Torbett is the senior author of the new report, which appears in the June 14, 2012 print issue of the Journal of Medicinal Chemistry.
HIV's nucleocapsid protein binds to the viral genome to package and protect it, and plays a key role in the assembly
of new virus copies, as well as in the reverse transcription of the viral genome into DNA. It has long been a target of HIV drug
developers because it grabs hold of the viral genome using protein structures-known as zinc knuckles-that can't change much
without losing their functionality. It thus is thought to have little room to mutate into drug-resistant forms, in contrast
with other HIV proteins
Screening Out Toxicity
However, despite almost two decades of research, there are still no FDA-approved drugs that target HIV's nucleocapsid protein
and its zinc knuckle structures. One reason is that similar structures exist on many healthy cellular proteins; thus compounds that target
them are apt to have unwanted side effects. "When researchers have targeted these nucleocapsid zinc knuckles in the past, they've usually
ended up producing toxicity," Torbett said.
To increase the chances of finding safe compounds, Torbett and his colleagues-postdoctoral researcher Sebastian Breuer,
the study's first author, and Max Chang and Jinyun Yuan, also postdoctoral researchers-began with the Maybridge HitFinder Collection,
a library of 14,400 chemical compounds from which many broadly toxic molecules have already been excluded. The Scripps Research
Molecular Screening Center maintains the latest robotic equipment for quickly applying chemical tests to such libraries.
With the help of screening expert Scripps Research Professor Hugh Rosen, Screening Center Staff Scientist Steven Brown,
and Research Assistant Jacqueline Lohse, Breuer applied a special combination of screening tests to the Maybridge
library to rapidly zero in on effective and safe nucleocapsid-inhibiting compounds.
The first screening test employed a technique known as fluorescence polarization to measure the ability of each compound in
the library to displace the binding of the viral genome to the nucleocapsid protein. (The study focused on the virus type HIV-1, which
accounts for the vast majority of HIV infections outside West Africa.) The second test, using differential scanning fluorimetry, was
applied to the 101 compounds that passed the first test; it identified those that perform the displacement by binding strongly to
the nucleocapsid protein rather than to the viral genome.
"We went very quickly from having a concept to having these two inhibitors with demonstrated anti-HIV activity in cells," said
Torbett.
Searching for the 'Sweet Spot'
With his Scripps Research colleagues M. G. Finn and Valery Fokin, Torbett now plans to evaluate compounds that are closely
related to the two inhibitors to see if the scientists can find any that are even more safe and effective. Torbett and colleagues also
plan to apply the same combination-screening method to larger compound libraries to identify entirely new nucleocapsid-inhibiting compounds.
To gain a better understanding of how these inhibitors work, Torbett is also collaborating with Scripps Research
structural biologists, including David Stout and Arthur Olson, and virologist John Elder to perform X-ray crystallography
studies of the inhibitors in combination with the HIV nucleocapsid protein.
"The overall goal here is to find a 'sweet spot' on the nucleocapsid protein that can be targeted effectively by a
small-molecule drug without causing toxicity," Torbett said.
For more information on the paper, "Identification of HIV-1 Inhibitors Targeting the Nucleocapsid Protein,"
see http://pubs.acs.org/doi/abs/10.1021/jm201442t
The study was supported by grants from the National Institutes of Health's National Institute of General Medical Sciences,
National Institute of Allergy and Infection Diseases, and National Heart, Lung and Blood Institute, as well as the California HIV/AIDS
Research Program.
About The Scripps Research Institute
The Scripps Research Institute is one of the world's largest independent, not-for-profit organizations focusing on research
in the biomedical sciences. Over the past decades, Scripps Research has developed a lengthy track record of major contributions to
science and health, including laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other
diseases. The institute employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned
scientists-including three Nobel laureates-work toward their next discoveries. The institute's graduate program,
which awards Ph.D. degrees in biology and chemistry, ranks among the top ten of its kind in the nation.
For more information, see www.scripps.edu.
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Source: http://www.scripps.edu/news/press/2012/20120613torbett.html
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