Navigation Links
UCSF researchers identify new drug target for Kaposi's sarcoma
Date:7/30/2009

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 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.


'/>"/>

Contact: Kristen Bole
kbole@pubaff.ucsf.edu
415-476-2557
University of California - San Francisco
Source:Eurekalert

Related biology news :

1. Fox Chase researchers uncover one force behind the MYC oncogene in many cancers
2. 1 in 6 health workers wont report in flu pandemic -- study by Ben-Gurion U. researchers
3. Researchers team up to provide new hope for childhood hunger
4. UBC researchers help push for standard DNA barcodes for plants
5. Researchers develop brain-reading methods
6. ISU researchers find possible treatment for spinal muscular atrophy
7. Researchers capture bacterial infection on film
8. Researchers design first model motor nerve system thats insulated and organized like the human body
9. Iowa State University researchers develop process for surgical genetic changes
10. UCLA researchers discover new molecular pathway for targeting cancer, disease
11. Munich researchers discover new target for tailored antibiotics
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:4/24/2017)... , April 24, 2017 Janice ... partner with  Identity Strategy Partners, LLP (IdSP) , ... or without President Trump,s March 6, 2017 ... Entry , refugee vetting can be instilled with greater ... (Right now, all refugee applications are suspended by ...
(Date:4/13/2017)... According to a new market research report "Consumer IAM Market by ... Service, Authentication Type, Deployment Mode, Vertical, and Region - Global Forecast to ... USD 14.30 Billion in 2017 to USD 31.75 Billion by 2022, at ... ... MarketsandMarkets Logo ...
(Date:4/6/2017)... , April 6, 2017 ... RFID, ANPR, Document Readers, by End-Use (Transportation & Logistics, ... Facility, Oil, Gas & Fossil Generation Facility, Nuclear Power), ... Educational, Other) Are you looking for a ... sector? ...
Breaking Biology News(10 mins):
(Date:10/11/2017)... ... October 11, 2017 , ... The CRISPR-Cas9 system ... experiments and avoiding the use of exogenous expression plasmids. The simplicity of programming ... systematic gain-of-function studies. , This complement to loss-of-function studies, such as with ...
(Date:10/11/2017)... the Netherlands and LAGUNA HILLS, Calif. ... The Institute of Cancer Research, London ... use MMprofiler™ with SKY92, SkylineDx,s prognostic tool to risk-stratify patients ... trial known as MUK nine . The University of ... trial, which is partly funded by Myeloma UK, and ICR ...
(Date:10/10/2017)... ... October 10, 2017 , ... ... antibody-drug conjugate (ADC) therapeutics, today confirmed licensing rights that give it exclusive ... a technology developed in collaboration with Children’s Hospital Los Angeles (CHLA). ...
(Date:10/10/2017)... ... October 10, 2017 , ... USDM Life Sciences , ... life sciences and healthcare industries, announces a presentation by Subbu Viswanathan and Jennifer ... “Automating GxP Validation for Agile Cloud Platforms,” will present a revolutionary approach to ...
Breaking Biology Technology: