Featured Research

from universities, journals, and other organizations

New Drug Target For Kaposi's Sarcoma

Date:
August 2, 2009
Source:
University of California - San Francisco
Summary:
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.

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.

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.


Story Source:

The above story is based on materials provided by University of California - San Francisco. Note: Materials may be edited for content and length.


Cite This Page:

University of California - San Francisco. "New Drug Target For Kaposi's Sarcoma." ScienceDaily. ScienceDaily, 2 August 2009. <www.sciencedaily.com/releases/2009/07/090730092938.htm>.
University of California - San Francisco. (2009, August 2). New Drug Target For Kaposi's Sarcoma. ScienceDaily. Retrieved April 20, 2014 from www.sciencedaily.com/releases/2009/07/090730092938.htm
University of California - San Francisco. "New Drug Target For Kaposi's Sarcoma." ScienceDaily. www.sciencedaily.com/releases/2009/07/090730092938.htm (accessed April 20, 2014).

Share This



More Health & Medicine News

Sunday, April 20, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Nine-Month-Old Baby Can't Open His Mouth

Nine-Month-Old Baby Can't Open His Mouth

Newsy (Apr. 19, 2014) Nine-month-old Wyatt Scott was born with a rare disorder called congenital trismus, which prevents him from opening his mouth. Video provided by Newsy
Powered by NewsLook.com
'Holy Grail' Of Weight Loss? New Find Could Be It

'Holy Grail' Of Weight Loss? New Find Could Be It

Newsy (Apr. 18, 2014) In a potential breakthrough for future obesity treatments, scientists have used MRI scans to pinpoint brown fat in a living adult for the first time. Video provided by Newsy
Powered by NewsLook.com
Little Progress Made In Fighting Food Poisoning, CDC Says

Little Progress Made In Fighting Food Poisoning, CDC Says

Newsy (Apr. 18, 2014) A new report shows rates of two foodborne infections increased in the U.S. in recent years, while salmonella actually dropped 9 percent. Video provided by Newsy
Powered by NewsLook.com
Scientists Create Stem Cells From Adult Skin Cells

Scientists Create Stem Cells From Adult Skin Cells

Newsy (Apr. 17, 2014) The breakthrough could mean a cure for some serious diseases and even the possibility of human cloning, but it's all still a way off. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins