Potions
from Poisons
Looking for new drugs
in unusual places
By ANDREA DORFMAN
If you're
prospecting for new drugs in nature - which scientists continue
to do, with or without the genome - there's no better place
to start than the business end of a good poisonous plant or
animal. Modern medicine is filled with drugs derived from
deadly poisons, from the muscle relaxant curare (taken from
South American vines that are used to poison arrow tips) to
the anticoagulant Aggrastat (based on the venom of the saw-scaled
viper).
The potency
of these compounds is no accident. After all, each is part
of an organism's defense and predatory mechanisms, whose specificity
has been honed over millions of years of evolution. Animal
venoms make particularly good sources of potential drugs because
they are designed to kill or immobilize prey. Many contain
dozens or even hundreds of potent, fast-acting toxins that
home in on the muscles and nervous system. The molecules also
tend to be small, which means they can easily slip across
the blood-brain barrier, the network of tiny vessels in the
brain that blocks larger compounds.
Poisonous
snakes, spiders, scorpions and frogs have so far attracted
the most scrutiny, but insects and marine creatures are also
rich sources of potent compounds. Here's a taste of what's
going on in the field.
Thailand
(Monocled) Cobra
The Thailand
cobra, which can grow to more than 6 ft., is armed with venom
that paralyzes nerves and muscles and eventually causes respiratory
arrest. For the past 10 years, PhyloMed Corp., of Plantation,
Fla., and the Bahamian firm Coral Pharmaceuticals have been
conducting clinical trials of Immunokine, a drug derived from
Thailand cobra venom, on people with multiple sclerosis. Virtually
nontoxic, Immunokine seems to prevent immune cells from attacking
and destroying the myelin sheath that protects nerve cells.
So far,
the results are encouraging. The drug works best on people
with the least nerve damage; its only apparent side effect
is that it exacerbates pms in some women. PhyloMed hopes to
launch a more advanced clinical trial on Canadian MS patients
early this year. Meanwhile, a British researcher has just
begun testing the drug's effectiveness against adrenomyeloneuropathy,
another debilitating central-nervous-system disorder.
Phantasmal
Poison-Dart Frog
In the
early 1990s, John Daly, a biochemist at the National Institutes
of Health, discovered that an extract from the skin of a tiny
Ecuadorian tree frog was a potent pain killer, some 200 times
more effective than morphine - at least in rats. The extract,
known as epibatidine, is structurally and functionally similar
to nicotine. It seems to prevent the nervous system from processing
pain signals by interfering with nicotinic receptors in the
brain.
When scientists
at Abbott Laboratories heard about Daly's research, they compared
epibatidine with several hundred related compounds they had
synthesized as experimental treatments for Alzheimer's disease.
One of them, ABT-594, turned out to be remarkably similar
but much less toxic. Tests on animals indicate that ABT-594
is about 50 times better than morphine in relieving both chronic
and acute pain yet seems to be nonaddictive. Phase II tests
on humans should be completed by the end of the year.
Southern
Copperhead
Scientists
have long known that venom from the southern copperhead, native
to the Eastern U.S. and Mexico, contains a powerful clot buster.
In the mid-1990s, a team led by biochemist Francis Markland,
of the University of Southern California, discovered that
the venom may also fight cancer.
The venom
contains a protein, contortrostatin, that retards the growth
and metastasis of tumors. Markland's team has found that injections
of contortrostatin not only prevent the spread of ovarian
and breast tumors in mice but also shrink them as much as
75%. The group hopes to start clinical trials of contortrostatin
in about two years.
Cone
Snail
The tropical
oceans harbor more than 500 species of cone snails, predatory
creatures that stab their prey with harpoons loaded with a
paralytic poison. Long prized by shell collectors, they are
being scrutinized by drug hunters for potential treatments
for neurological and neuromuscular disorders.
Each species
of cone snail produces a unique venom that contains between
50 and 200 pharmacologically active peptides known as conotoxins.
The most advanced conotoxin-derived drug in development is
Elan Corp.'s Ziconotide, a nonaddictive treatment for severe
chronic pain that is awaiting fda approval. Cognetix, based
in Salt Lake City, Utah, recently started clinical trials
on a possible epilepsy treatment. Also in the works: potential
therapies for schizophrenia, stroke and Parkinson's and Alzheimer's
diseases.
Terciopelo
Snake (Fer-de-Lance)
Pit-viper
venoms - particularly those from the genus Bothrops, of which
the Central American terciopelo snake is a member - contain
compounds that closely resemble substances used by white blood
cells to fend off bacterial infections. Some of these substances
work by damaging or disrupting lipids within the bacterial
cell wall. A decade ago, microbiologists Edgardo Moreno, of
Costa Rica's National University, and Bruno Lomonte, of the
University of Costa Rica, realized that a muscle-destroying
toxin in terciopelo venom behaved the same way.
The two
scientists have since isolated at least 10 microbe-fighting
myotoxins from various viper venoms and synthesized nontoxic
versions of them in the lab. They are talking to drug companies
about doing additional research in animals and, eventually,
people. If those studies pan out, Moreno says, viper-venom
antibiotics could be put in everything from mouthwashes to
contact lenses to fight salmonella, cholera, staph and strep.
Giant
Israeli Scorpion
Chlorotoxin,
a substance in the venom of the giant Israeli scorpion, a
5-in.-long species known as the "death stalker," may offer
hope for the 25,000 Americans each year who have glioma, an
incurable, rapidly spreading form of brain cancer. Surgery
provides only a temporary respite, and the few experimental
therapies extend a patient's life span only weeks.
Identified
by neurobiologist Harald Sontheimer, of the University of
Alabama at Birmingham, chlorotoxin targets glioma cells and
blocks their fluid-balancing chloride channels, preventing
them from shrinking and then migrating elsewhere in the brain.
Sontheimer's group is about to submit a clinical-trial protocol
to the fda. If approved, as many as 30 glioma patients could
begin receiving chlorotoxin tagged with radioactive iodine
as early as July. If the strategy works, Sontheimer says,
"chlorotoxin could become a platform for delivering all sorts
of drugs."
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January 15, 2001
| No. 2
COVER
STORIES
MEDICINE:
The Future of Drugs
Now that our dna has been decoded, the search for better, faster and more
effective medications begins in earnest
THE
LABS: Inside the Brave New Pharmacy
At a leading genomics company, the star of the show is a robot
DISEASES:
The Search for Cures
For AIDS, cancer, mental illness, obesity, Alzheimer's, etc.
Antibiotics:
The microbes are winning
Delivery:
Beyond pills and needles
Natural remedies:
Turning poisons into potions
Recreational
drugs: What comes after K and ecstasy?
THE
YEAR IN MEDICINE: An A-to-Z guide
T
H E A R T S
CINEMA:
East meets West
in a film with universal appeal
Robert de Niro and Ben Stiller team up in a funny
farce
Three generations of Ralph Fiennes in Sunshine
MUSIC:
Erykah Badu's new CD has soul and guts
TRAVELER'S
ADVISORY
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