Drug Dials Down The Energy Within Cells, UM Researchers Find

[Guest guest]

Drug Dials Down The Energy Within Cells, UM Researchers Find

http://www.medicalnewstoday.com/medicalnews.php?newsid=46641

A drug effective at treating animal models of human autoimmune

disorders and other diseases works by dialing down the activity of a

key enzyme involved in energy production, University of Michigan

researchers have found.

" Many drugs block the function of enzymes, essentially turning them

off, " said Glick, who is the Werner E. Bachmann Collegiate

Professor of Chemistry at U-M. " Our compound works more like a volume

control, so we're able to dial enzyme activity down to a level that

maintains normal function while simultaneously allowing for

initiation of a process that selectively kills or disables disease-

causing cells. "

Glick and collaborators published their findings in the June 16 issue

of ACS Chemical Biology.

The drug, discovered by Glick and coworkers and called benzodiazepine-

423 (Bz-423), is a chemical cousin of anti-anxiety medications such

as Valium and Xanax. In previous work, Glick's group showed that Bz-

423 reduces effects of arthritis and the autoimmune disease lupus in

mice and may be useful in treating psoriasis. Unlike conventional

drugs for these conditions, which can't discriminate between healthy

and disease-causing cells, Bz-423 is highly selective, homing in on

disease-causing cells.

In an attempt to better exploit its therapeutic properties, the

researchers have been studying the details of Bz-423's activity. They

learned that the compound targets an enzyme inside mitochondria, the

energy factories of cells. The specific enzyme, F1F0-ATPase, is

responsible for producing most of the cell's ATP. That's a critical

role because ATP, often referred to as the cell's energy currency, is

the molecule that captures chemical energy from food and transfers it

to energy-demanding processes, such as muscle contraction and the

transmission of nerve signals.

" People had proposed in the past that if you could inhibit this

enzyme, there might be therapeutic potential. But the problem is, if

you inhibit the enzyme in the way most powerful drugs do, turning it

off, you deplete the cell of ATP, and that's fatal, " Glick said. " Our

new work reveals the mechanism by which Bz-423 inhibits the enzyme

while still allowing it to function. This is important because it

suggests principles that may be useful for targeting other

bioenergetic pathways. Now we have some rules that we can apply to be

able to modulate the mitochondria in new ways that could be

therapeutic. "

Ultimately, the findings may have applications not only for lupus,

arthritis and psoriasis, but also for other conditions, Glick

believes. " There are other diseases---certain cancers and a number of

other immune diseases---where we think the way the cells make and

utilize energy is fundamental to the disease process. Combining that

knowledge with our new knowledge of how to regulate the energy of the

cell could open up new avenues for treating disease and monitoring

the effectiveness of treatment. "

###

Glick collaborated on the research with Carol Fierke, who is the

Jerome and Isabella Karle Collegiate Professor of Chemistry;

Opipari, Jr., associate professor of obstetrics and gynecology;

graduate student and postdoctoral fellow Joanne

Cleary. The researchers received funding from the National Institutes

of Health.

For more information:

Glick

http://www.chembio.umich.edu/people/glick.html

ACS Chemical Biology

http://pubs.acs.org/journals/acbcct/index.html

Previous news releases about Bz-423:

" New compound holds promise for treating lupus and related diseases "

http://www.umich.edu/news/index.html?Releases/2002/Oct02/chr101602a

" Novel drug fights autoimmune disorders "

http://www.umich.edu/news/index.html?Releases/2003/Mar03/r030303c

" Chemical cousin of anti-anxiety drugs holds promise for psoriasis

treatment "

http://www.umich.edu/news/index.html?Releases/2004/Dec04/r120804a