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Scorpion Venom Research May Lead to New Drugs That Treat Immune

Disorders, Aid Transplants

July 6, 2000 Proceedings of the National Academy of

Sciences/MedscapeWire

A new, synthesized chemical that affects cells similarly to scorpion

venom also can effectively suppress the immune system, a University of

California at Irvine College of Medicine research team has found.

The chemical eventually could be used as a drug to assist with organ

transplants and also treat disorders like lupus, multiple sclerosis, and

rheumatoid arthritis in which the immune system causes the body to

attack itself, possibly without the severe adverse effects of existing

anti-immune drugs. The findings appear in the July 5 issue of the

Proceedings of the National Academy of Sciences.

Heike Wulff, postdoctoral researcher with department of physiology and

biophysics, synthesized the chemical, called TRAM-34, and found that it

binds to a channel located on T cells. TRAM-34 suppressed the activation

of these T cells and prevented them from proliferating and performing

their normal job of triggering immune responses to foreign objects. This

normal immune response protects the body against disease but also can

cause the body to reject transplanted organs and, in certain diseases of

immunity, induce the body to attack itself.

Scorpion venom stuns prey or wards off predators with poisonous effect,

and the researchers used the venom's characteristics as an initial guide

to develop a chemical with gentler, more therapeutic properties.

" From a study that started originally by looking at how scorpion venom

inactivated cell functions, we synthesized the chemical TRAM-34 and

found it suppressed T-cell function without affecting other biochemical

processes in the cell, " said Wulff. " If TRAM-34 proves effective in

humans, we think it may be an effective way to keep the immune system

from attacking itself in certain diseases or from rejecting transplanted

organs. "

The team found that TRAM-34 inhibited T cells by blocking a cell

membrane channel called IKCa1, the same channel that is blocked by the

scorpion venom. This channel is found on all T cells; blocking it

appears to curb the T cell's ability to coordinate the body's attack

against bacteria, viruses, and other foreign bodies.

In addition, TRAM-34 did not block the action of other important enzymes

in the body, which indicates that the chemical may not produce the

adverse effects of other drugs either being used or currently in

clinical trials for treating immune disorders and assisting organ

transplants. Both cyclosporin, which suppresses the immune system and is

now used in transplant surgery, and clotrimazole, an antifungal drug

being tested for sickle cell anemia and considered for future tests as

an immunosuppressant, can cause adverse effects such as gastrointestinal

and urinary system problems.

" Because TRAM-34 very specifically blocks only the IKCa1 channel and

doesn't affect other functions in the cell that are affected by other

drugs, we believe it may result in a drug that has fewer side effects, "

said Wulff. " Just as we used scorpion venom only as a jumping-off point

to look for a possible drug that uses the same receptor, we're now

looking to see if TRAM-34 points us to better treatments for immune

system disorders. "

The team is now working to determine whether TRAM-34 could be developed

as a pharmaceutical agent and if other chemicals similar to TRAM-34 work

as effectively at suppressing the immune system.

Wulff is one member of a group of researchers at the University of

California at Irvine who, as part of their efforts to create treatments

from chemicals that bind to a variety of T-cell channels, are looking at

how channels' functions can be discerned by observing their interactions

with animal venom and other chemicals.

Recently, the group found that chemicals related to sea anemone toxin

also have an effect on another T-cell channel and may be able to provide

yet another group of treatments against immune system disorders.

Proc Natl Acad Sci USA. 2000;97:8151-8156