Protease Inhibitors And Cancer

Somebody should give a shout out to Dr. Troll of New York
University .. who FIRST .. discovered these as reported by .. me ..
many years .. ago ..
I believe it is .. niacin .. a natural protease inhibitor ..
Dr. Troll must be a .. scientologist ..

UCSF researchers identify new drug target for Kaposi's sarcoma
Science Centric | 30 July 2009 16:09 GMT

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.