Navigation Links
New drug-screening method yields long-sought anti-HIV compounds

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 structuresknown as zinc knucklesthat 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 colleaguespostdoctoral researcher Sebastian Breuer, the study's first author, and Max Chang and Jinyun Yuan, also postdoctoral researchersbegan 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.

After eliminating the weaker and more toxic candidates with further tests, Breuer, Torbett, and their colleagues ended up with 10 compounds. Detailed analyses of these yielded two that were sufficiently powerful at inhibiting viral infectivity in cell culture tests, without being unacceptably toxic.

"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.


Contact: Mika Ono
Scripps Research Institute

Related biology news :

1. New 3-D stem cell culture method published in JoVE
2. New methods for better purification of wastewater
3. More effective method of imaging proteins
4. New method for estimating parameters may boost biological models
5. New paper by Notre Dame researchers describes method for cleaning up nuclear waste
6. Scientists discover new method of proton transfer
7. Oceanographers develop method for measuring the pace of life in deep sediments
8. Notre Dame researchers using novel method to combat malaria drug resistance
9. Rapid method of assembling new gene-editing tool could revolutionize genetic research
10. Scientists advance field of research with publication of newly validated method for analyzing flavanols in cocoa
11. Chemical engineers at UMass Amherst find high-yield method of making xylene from biomass
Post Your Comments:
Related Image:
New drug-screening method yields long-sought anti-HIV compounds
(Date:6/16/2016)... 16, 2016 The global ... to reach USD 1.83 billion by 2024, according ... Inc. Technological proliferation and increasing demand in commercial ... to drive the market growth.      ... The development of advanced multimodal techniques for biometric ...
(Date:6/9/2016)...  Perkotek an innovation leader in attendance control systems is proud to announce the ... employers to make sure the right employees are actually signing in, and to even ... ... ... ...
(Date:6/7/2016)... , June 7, 2016  Syngrafii Inc. ... a business relationship that includes integrating Syngrafii,s patented ... branch project. This collaboration will result in greater ... the credit union, while maintaining existing document workflow ... ...
Breaking Biology News(10 mins):
(Date:6/27/2016)... -- Liquid Biotech USA , Inc. ... Research Agreement with The University of Pennsylvania ("PENN") ... patients.  The funding will be used to assess ... outcomes in cancer patients undergoing a variety of ... to support the design of a therapeutic, decision-making ...
(Date:6/24/2016)... (PRWEB) , ... June 24, 2016 , ... Researchers at ... most commonly-identified miRNAs in people with peritoneal or pleural mesothelioma. Their findings are the ... read it now. , Diagnostic biomarkers are signposts in the blood, lung fluid ...
(Date:6/23/2016)... SILVER SPRING, Md. , June 23, 2016 ... evidence collected from the crime scene to track the criminal ... sick, and the U.S. Food and Drug Administration (FDA) uses ... Sound far-fetched? It,s not. ... whole genome sequencing to support investigations of foodborne illnesses. Put ...
(Date:6/23/2016)... , June 23, 2016   EpiBiome , ... secured $1 million in debt financing from Silicon Valley ... up automation and to advance its drug development efforts, ... new facility. "SVB has been an incredible ... the services a traditional bank would provide," said Dr. ...
Breaking Biology Technology: