Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

UCSF researchers identify new drug target for Kaposi’s Sarcoma

03.08.2009
UCSF researchers have identified a new potential drug target for the herpes virus that causes Kaposi’s sarcoma, re-opening the possibility of using the class of drugs called protease inhibitors against the full herpes family of viruses, which for 20 years has been deemed too difficult to attain.

The new drug target, which is known as a protease dimer, could serve as a model for developing new therapeutics for diseases ranging from cancer to Alzheimer’s, the researchers say. Findings are reported in the Advance Online Publication section of the “Nature Chemical Biology” web site and can be found at http://www.nature.com/nchembio/index.html .

Most current antiviral drugs target the active sites of viral proteins, where enzymes and receptors work in a lock-and-key approach to either activate or deactivate that particular protein, the researchers explained. Traditionally, drug development has focused on inhibiting that lock-and-key action to prevent the enzyme, or receptor from being effective.

Some viral enzymes known as proteases, however, including those for HIV and the herpes virus family, take the form of a dimer, or two identical halves – much like a fully opened clamshell – in their most stable state. Those proteases play an essential role in making the virus infectious, but require the two clamshell halves to bind together to be activated, according to the paper.

The HIV protease was successfully targeted for drug development in the 1980s, by blocking the active site on the surface of the dimer, but the herpes virus protease dimer has consistently eluded efforts to disrupt it at its active site, the researchers said.

The UCSF team set out to find ways to instead prevent the two halves of the dimer from connecting at that clamshell joint, to prevent it from activating. What they found was a new target on the unstable, monomer form of the protease, which responded well to a chemical inhibitor.

“If you disrupt the protein-protein interactions, you don’t need the key to a specific lock,” said Charles S. Craik, PhD, senior author on the paper and a professor of pharmaceutical chemistry in the UCSF School of Pharmacy. “Instead, we’re essentially preventing the lock from being made in the first place.”

Craik, who also led a team that identified HIV protease inhibitors in the late 1980s, said the “Nature Chemical Biology” paper validates this new site as a viable option for small-molecule drugs to treat Kaposi’s, as well as other members of this viral family.

“All known herpes virus proteases are structurally similar,” Craik explained. “The inhibitor we found knocks out not only KS, but also the cytomegalovirus protease, so the site we’ve identified here could be a target for a broad-acting inhibitor against the entire viral family.”

To their knowledge, the researchers said, this is the first small-molecule inhibitor of a herpes virus protease to not only act outside the active site, but also to select for the partially unfolded protein to keep it from forming the dimer interface.

Herpes viruses make up one of the most prevalent viral families, including eight human viruses that cause a variety of devastating illnesses, the researchers said. Those include mononucleosis (Epstein-Barr virus), shingles (Varicella zoster virus), genital herpes (herpes simplex), retinitis (cytomegalovirus) and cancer (Kaposi’s sarcoma). While therapies exist for these viruses, they often have negative side effects and are facing rising viral resistance.

In addition to validating herpes virus proteases as suitable targets, Craik said this research was also among the first to use computational design to identify and create a potential drug to target that protease interface.

Using high-throughput screening, the team screened a library of 182 compounds that it had specifically and rationally designed to mimic the protease interface. The work identified six molecules that inhibited the Kaposi’s sarcoma virus protease activity by at least 50 percent, including one that was highly potent.

That discovery potentially opens myriad opportunities for drug discovery, Craik said, by making target receptors that were biologically validated, but then deemed undruggable, more attractive. Protein-protein interactions have been researched as drug targets against a range of diseases, from certain cancers to neurodegenerative diseases. This advance could enable researchers to reconsider those targets, he said.

The lead investigator on the paper was Tina Shahian, with the Graduate Group in Biochemistry and Molecular Biology at UCSF. Co-authors were Gregory M. Lee and Ana Lazic, both in the UCSF Department of Pharmaceutical Chemistry; and Leggy A. Arnold, Priya Velusamy, Christina M. Roels and R. Kiplin Guy, all with the Department of Chemical Biology and Therapeutics at St. Jude Children’s Research Hospital, Memphis, TN.

The CMV protease expression plasmid for this work was provided by Wade Gibson, a professor in the Department of Pharmacology and Molecular Sciences at Johns Hopkins School of Medicine. The work was funded by grants from the National Institutes of Health, the American Lebanese and Syrian Associated Charities and St. Jude Children’s Research Hospital.

The authors declare no conflict of interest in this paper.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. For further information, visit http://www.ucsf.edu.

Kristen Bole | EurekAlert!
Further information:
http://www.ucsf.edu
http://www.nature.com/nchembio/index.html

More articles from Life Sciences:

nachricht Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz

nachricht Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Fighting drug resistant tuberculosis – InfectoGnostics meets MYCO-NET² partners in Peru

28.04.2017 | Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

 
Latest News

Wireless power can drive tiny electronic devices in the GI tract

28.04.2017 | Medical Engineering

Ice cave in Transylvania yields window into region's past

28.04.2017 | Earth Sciences

Nose2Brain – Better Therapy for Multiple Sclerosis

28.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>