Brave
New Pharmacy
PAGE
1 | 2
| 3 | 4
In 1998, Tepper's team used this reasoning to try to improve on the popular
blood-pressure-lowering drugs known as ace inhibitors. These compounds inhibit
an enzyme called angiotensin-converting enzyme (ace), which is responsible for
making the muscle cells in blood vessels contract, which drives blood pressure up.
By interfering with the activity of this enzyme, ace inhibitors keep blood vessels
relaxed and pressure down.
But the ace inhibitors currently on the market don't work on everyone, and
Millennium figured that the genome might help them find a better version. So
researchers sat down at their computers, plugged in some genetic sequences
found in the gene for ace and came up with 10,000 genes that might have
comparable activity.
Then they used Zeus to set up microarray analyses and winnowed the 10,000
down to one promising protein they call ace-2. Testing the enzyme on tissue cells
from different organs in the body, the scientists showed that whereas the original
ace acts broadly on many tissues in the body, ace-2 is particularly active in heart
and kidney cells, where it might be more effective in controlling high blood
pressure. Because they already knew on the molecular level exactly how ace
worked, Tepper's team also knew precisely which lab tests would determine
whether ace-2 had the same effects.
It did, so they moved quickly to develop a compound that inhibits ace-2.
Scientists combed through Millennium's library of 700 different classes of
compounds for molecules whose chemistry made them candidates to clamp down
on ace-2 activity. Then, with the help of protein-modeling software (see
Bioinformatics box), they manipulated the chemical structure of their new
inhibitor to give it optimal binding affinity with the ace-2 receptor. In about two
years, Millennium had created a new blood-pressure-drug candidate that is now
being tested in animals.
The last step for the ace-2 inhibitor, as for any drug, is human clinical trials.
Because the Food and Drug Administration requires such rigorous testing, this is
by far the most expensive part of drug development. So for human trials in some
cases, Millennium has formed partnerships with large pharmaceutical companies
that have the necessary resources and will share in any eventual profits.
Everyone looking for new drugs, whether genomically or in more traditional
ways, wants to reduce the cost of bringing a medication to market - now
estimated at $500 million. One way to do it is to limit trials to those people most
likely to respond to a given drug. This too is governed by genetics. Says Ira
Herskowitz, a biochemist and biophysicist at the University of California, San
Francisco: "We're all different, we have different hair color and different features,
right? How can we not metabolize drugs differently?"
That's why Herskowitz and his colleagues have launched a project to unravel
exactly what - at the genetic level - makes some people benefit from drugs and
others not. They suspect that one major factor is a class of proteins called
membrane transporters. These proteins act as molecular gatekeepers, deciding
which foreign substances in the bloodstream will be taken into and which rejected
by individual cells. If, for example, people lack the gene for an inactivating
enzyme, says Herskowitz, "a standard dose of a drug will be more potent. If they
have an extra copy of the gene, a standard dose will be inadequate."
To get a handle on how these proteins vary from one person to the next, members
of the Pharmacogenetics of Membrane Transporters project are focusing on 25
different transporters already known to play a role in drug absorption and
elimination. The first step is to look at the genes for those transporters in DNA
samples from 250 ethnically diverse people and see how they vary from one
individual to the next. "Identifying the variants is rather easy," says Kathleen
Giacomini, the project's principal investigator and ucsf's chairwoman of
biopharmaceutical sciences. "The really hard part is in looking at whether the
variants have significance for drug response."
That requires working with living cells. The researchers insert different versions
of a given gene into a cell and see how its response to a particular body chemical
- serotonin, for example, a neurotransmitter implicated in clinical depression -
varies. Then they bathe the cells in Prozac, for instance, which works by
modifying serotonin levels in the brain, and see how that response changes. "If
there's a difference," says Giacomini, "I'll know that maybe your transporter
interacts with the drugs a little differently from mine."
As of this month, ucsf researchers have done about 20% of
the initial DNA analysis and have found more than a dozen
variants, which are now being screened in cells. The scientists
on tap to look for variants that haven't been analyzed yet,
says Herskowitz, "are chomping at the bit, saying, 'When is
my gene going to be done?'" MORE>>
PAGE 1 | 2
| 3 | 4
|
|
|
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
|
|
