Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

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

14.06.2012
The drug candidates act on a target unlikely to mutate

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.

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.

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.

Mika Ono | EurekAlert!
Further information:
http://www.scripps.edu

More articles from Life Sciences:

nachricht New type of photosynthesis discovered
17.06.2018 | Imperial College London

nachricht New ID pictures of conducting polymers discover a surprise ABBA fan
17.06.2018 | University of Warwick

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: AchemAsia 2019 will take place in Shanghai

Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.

Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...

Im Focus: First real-time test of Li-Fi utilization for the industrial Internet of Things

The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.

Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.

Im Focus: Sharp images with flexible fibers

An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.

Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...

Im Focus: Photoexcited graphene puzzle solved

A boost for graphene-based light detectors

Light detection and control lies at the heart of many modern device applications, such as smartphone cameras. Using graphene as a light-sensitive material for...

Im Focus: Water is not the same as water

Water molecules exist in two different forms with almost identical physical properties. For the first time, researchers have succeeded in separating the two forms to show that they can exhibit different chemical reactivities. These results were reported by researchers from the University of Basel and their colleagues in Hamburg in the scientific journal Nature Communications.

From a chemical perspective, water is a molecule in which a single oxygen atom is linked to two hydrogen atoms. It is less well known that water exists in two...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Munich conference on asteroid detection, tracking and defense

13.06.2018 | Event News

2nd International Baltic Earth Conference in Denmark: “The Baltic Sea region in Transition”

08.06.2018 | Event News

ISEKI_Food 2018: Conference with Holistic View of Food Production

05.06.2018 | Event News

 
Latest News

A sprinkle of platinum nanoparticles onto graphene makes brain probes more sensitive

15.06.2018 | Materials Sciences

100 % Organic Farming in Bhutan – a Realistic Target?

15.06.2018 | Ecology, The Environment and Conservation

Perovskite-silicon solar cell research collaboration hits 25.2% efficiency

15.06.2018 | Power and Electrical Engineering

VideoLinks
Science & Research
Overview of more VideoLinks >>>