In case anyone is interested, here's a lengthy article from the SJ Mercury News yesterday, which mentions Amylin and Exendin (for a change)...
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FROM the fangs and stingers of nature's most poisonous predators --
creatures like tarantulas, scorpions and Gila monsters -- something very
unlikely is flowing:
Medicine.
The venom those animals use to paralyze and kill their prey contains unique
chemicals that may help relieve chronic pain in humans, prevent brain damage
from stroke and treat diabetes. Those chemicals also are becoming invaluable
tools for scientists studying the brain and nervous system -- two places where
animal venoms inflict their damage.
People have speculated for years that venoms might have medicinal use
because they are so concentrated and powerful -- a few drops from some
spiders and snakes can quickly kill many animals and in some cases humans.
But only after recent advances in chemistry and biotechnology has venom
moved from folk medicine toward the real thing.
''The venoms are very important for all the creatures who produce them
because that's the only way they can survive,'' said Roberto Crea, senior vice
president for research and technology development at Neurex Corp. in Menlo
Park, one of the leading companies working with venoms. ''You can think of
the work nature has done in millions of years of evolution to develop something
that acts very quick and very effectively on something else.''
Trying to seize on that work, Neurex has a pain medication in the final stage of
human tests that is derived from the venom of a snail found off the coast of the
Philippines. Three weeks ago, company scientists announced they had isolated
a compound from the venom of a West African tarantula that could play a key
role in developing new treatments for brain and neurological disorders.
Neurex is among about a dozen biotechnology and pharmaceutical companies
working to find new drugs among the stew of substances -- some poisonous,
but many not -- found in each type of venom. University scientists are also on
the case.
''There is a great diversity of compounds in venom; it's a very rich source of
different molecules,'' said Dr. Andrew Young, vice president of physiology at
Amylin Pharmaceuticals in San Diego, which is developing a diabetes
medication derived from the venom of Gila monster lizards.
Those diverse compounds are an evolutionary mechanism to prevent animals
from gaining immunity to the venom, he said. If the prey becomes immune to
one compound, the others would still work. So floating along with the poisons
are all kinds of unique, powerful chemicals that could perform important tasks
in the human body.
Venom is just the latest in a line of natural substances humans have mined for
medicine. First came herbs and plants, the source of numerous drugs, from
aspirin (derived from the bark of the willow tree) to morphine (a derivative of
the opium poppy). Then about 50 years ago, scientists learned how to exploit
antibiotic-producing microorganisms, such as the molds that gave us penicillin.
But venoms have been harder to harness, said Dr. George Miljanich, senior
director of biochemistry at Neurex who began studying venom in 1982 as a
professor at the University of Southern California.
''People have used venoms, venom glands and venomous animals as kinds of
folk remedies for centuries,'' Miljanich said. An Italian remedy, for example,
involved putting scorpions in olive oil, then drinking the whole concoction.
Those crude methods failed because the active substances in venoms are
peptides -- chemicals that get destroyed by the acids in the stomach and
digestive tract. Insulin, for example, is a hormone consisting of two groups of
peptides, which is why diabetics must inject it into their bloodstream rather than
swallow it.
Animals that use venom have developed their own natural hypodermic needles
-- snake fangs or scorpion stingers to name a couple -- to inject the poison
directly into their prey.
Once inside the animal the venom has to work quickly to subdue the prey
before it fights back. That means the venom has to specifically target certain
functions in the body, get to them quickly and disable them immediately.
One such animal is a type of snail found in the coral reefs off the coast of the
Philippines. This two-inch snail of the Conus species kills small fish with a
harpoon-like stinger that injects a venom so powerful it has killed dozens of
hapless shell collectors lured by the snail's beautiful colors.
Baldomero Olivera, a biology professor at the University of Utah, grew up in
the Philippines and returned to his country about 30 years ago to study the
snails' poisonous venom.
He and his colleagues thought analyzing it would be simple.
''We had sort of expected there would only be one thing in there that would
have a real potent activity,'' said Olivera, who earned his doctorate at the
California Institute of Technology and did postdoctoral research at Stanford
University. ''Then we began to realize that there were lots of . . . active
ingredients in the venom, and it gradually dawned on us that some of these
could be useful in doing drug discovery.''
He was right. One of the substances found among the more than 100 different
chemicals in the venom of the Conus magus snail affects a key function in
nervous-system cells involved with transmitting pain.
In fish, that function -- specifically a channel that carries calcium to cells -- is
also connected with breathing, and the substance helps smother the fish. But in
humans, the venom derivative blocks only pain, said Paul Goddard, chairman
and chief executive officer of Neurex.
The company's pain drug, SNX-111, using a synthetic version of the venom
substance, shows the advantages of a potent venom chemical that is very
focused inside the body. SNX-111 blocks a specific calcium channel involved
only with the transmission of pain signals to the brain. So unlike other pain
medications, such as morphine, it doesn't numb the body to other sensations,
like warmth or cold.
The drug is administered through an implantable pump near the spine. It is
being tested on those suffering chronic pain from diseases such as cancer and
should be submitted to the Food and Drug Administration for approval next
year, Goddard said. If approved, it would join another venom-derived drug on
the market -- captopril, a high blood pressure medication originally derived
from the venom of the Brazilian pit viper.
SNX-111 also is being tested as a way of disabling nerve cells in the brain
shortly after a head injury to prevent brain damage.
At Amylin Pharmaceuticals, researchers are testing a substance found in Gila
monster venom that, like many things found in venom, may have had some use
long ago but now appears to play no role. For some reason, the substance is
similar to a human protein that stimulates the secretion of insulin. Drug
companies have tried for years to create a substance to do that for diabetics,
Young said, but haven't been able to find anything that works for more than a
few minutes. And that's not long enough.
''Here, nature has done something that the pharmaceutical companies were
unable to do, which is provide a long-acting mimic of a human hormone,'' he
said. Amylin's venom derivative, called Exendin, works for several hours. The
company hopes to start human tests on the drug next year for people with
elderly onset diabetes.
But much of the value of venoms now, and in the future, involves using them as
research tools to determine how certain parts of the body work.
The substance Neurex scientists found in the venom of the Cameroon red
tarantula is the first substance that specifically blocks another type of calcium
channel in the brain and nervous system, Crea said. Being able to block that
channel should help scientists figure out what role that channel plays in the
neurological system.
''We essentially purchase from many sources around the world venom from
spiders, sea snails, snakes and so on,'' he said. Then Neurex screens those
venoms for compounds that do a specific task.
The same type of research is going on in the laboratory of Michael Adams, a
professor of neuroscience and entomology at the University of
California-Riverside.
In the venom of the funnel web spider, an arachnid common to the
southwestern United States, Adams and his colleagues found proteins that
block another type of calcium channel in the brain.
''They're helping us to find the physiological functions of different calcium
channels drug companies want to target,'' he said.
Such research, growing in the past five years, has created customers for people
like Brian Whitely, who milks the venom from spiders in his home in the Santa
Cruz Mountains and ships it to researchers in dry ice. His small company,
Invertebrate Biologics, is one of several from which scientists can get venoms
without having to tangle with the animals themselves.
Whitely raises spiders as a hobby and has been selling the venom for a few
years. He has about a dozen customers and hopes the increasing interest in
venom research will turn his business into a lucrative one.
''They're fabulous tools for research because of their incredibly specificity and
potency,'' Miljanich said of venoms. ''They're use in research so far has
outstripped their use as medicine, but I think medicine is going to catch up.''
Published Tuesday, November 18, 1997, in the San Jose Mercury News
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