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发表于 2002-5-11 09:03
| From: Scientific American
www.sciam.com\2001\1101issue\1101haseltine.html
Beyond Chicken Soup
The antiviral era is upon us, with an array of virus-fighting drugs on
the market and in development. Research into viral genomes is
fueling much of this progress
By William A. Haseltine
Back in the mid-1980s, when scientists first learned that a virus
caused a relentless new disease named AIDS, pharmacy shelves
were loaded with drugs able to treat bacterial infections. For viral
diseases, though, medicine had little to offer beyond chicken soup
and a cluster of vaccines. The story is dramatically different today.
Dozens of antiviral therapies, including several new vaccines, are
available, and hundreds more are in development. If the 1950s were
the golden age of antibiotics, we are now in the early years of
the golden age of antivirals.
This richness springs from various sources. Pharmaceutical
companies would certainly point to the advent in the past 15 years of
sophisticated techniques for discovering all manner of drugs. At the
same time, frantic efforts to find lifesaving therapies for HIV, the
cause of AIDS, have suggested creative ways to fight not
only HIV but other viruses, too.
A little-recognized but more important force has also been at work:
viral genomics, which deciphers the sequence of "letters," or nucleic
acids, in a virus's genetic "text." This sequence includes the letters in
all the virus's genes, which form the blueprints for viral proteins;
these proteins, in turn, serve as the structural elements and the
working parts of the virus and thus control its behavior. With a full
or even a partial genome sequence in hand, scientists can quickly
learn many details of how a virus causes disease--and which stages
of the process might be particularly vulnerable to attack. In 2001 the
full genome of any virus can be sequenced within days, making it
possible to spot that virus's weaknesses with unprecedented speed.
The majority of antivirals on sale these days take aim at HIV,
herpesviruses (responsible for a range of ills, from cold sores to
encephalitis), and hepatitis B and C viruses (both of which can cause
liver cancer). HIV and these forms of hepatitis will surely remain a
main focus of investigation for some time; together they cause more
than 250,000 cases of disease in the U.S. every year and millions in
other countries. Biologists, however, are working aggressively to
combat other viral illnesses as well. I cannot begin to describe all the
classes of antivirals on the market and under study, but I do hope this
article will offer a sense of the extraordinary advances that genomics
and other sophisticated technologies have made possible in recent
years.
Drug-Search Strategies
The earliest antivirals (mainly against herpes) were introduced in the
1960s and emerged from traditional drug-discovery methods.
Viruses are structurally simple, essentially consisting of genes and
perhaps some enzymes (biological catalysts) encased in a protein
capsule and sometimes also in a lipid envelope. Because this design
requires viruses to replicate inside cells, investigators infected cells,
grew them in culture and exposed the cultures to chemicals that
might plausibly inhibit viral activities known at the time. Chemicals
that reduced the amount of virus in the culture were considered for
in-depth investigation. Beyond being a rather hit-or-miss process,
such screening left scientists with few clues to other viral activities
worth attacking. This handicap hampered efforts to develop drugs
that were more effective or had fewer side effects.
Genomics has been a springboard for discovering fresh targets for
attack and has thus opened the way to development of whole new
classes of antiviral drugs. Most viral targets selected since the 1980s
have been identified with the help of genomics, even though the term
itself was only coined in the late 1980s, well after some of the
currently available antiviral drugs were developed.
After investigators decipher the sequence of code letters in a given
virus, they can enlist computers to compare that sequence with those
already identified in other organisms, including other viruses, and
thereby learn how the sequence is segmented into genes. Strings of
code letters that closely resemble known genes in other organisms
are likely to constitute genes in the virus as well and to give rise to
proteins that have similar structures. Having located a virus's genes,
scientists can study the functions of the corresponding proteins and
thus build a comprehensive picture of the molecular steps by which
the virus of interest gains a foothold and thrives in the body.
That picture, in turn, can highlight the proteins--and the domains
within those proteins--that would be good to disable. In general,
investigators favor targets whose disruption would impair viral
activity most. They also like to focus on protein domains that bear
little resemblance to those in humans, to avoid harming healthy cells
and causing intolerable side effects. They take aim, too, at protein
domains that are basically identical in all major strains of the virus,
so that the drug will be useful against the broadest possible range of
viral variants.
After researchers identify a viral target, they can enlist various
techniques to find drugs that are able to perturb it. Drug sleuths can,
for example, take advantage of standard genetic engineering
(introduced in the 1970s) to produce pure copies of a selected protein
for use in drug development. They insert the corresponding gene into
bacteria or other types of cells, which synthesize endless copies of
the encoded protein. The resulting protein molecules can then form
the basis of rapid screening tests: only substances that bind to them
are pursued further.
Alternatively, investigators might analyze the three- dimensional
structure of a protein domain and then design drugs that bind tightly
to that region. For instance, they might construct a compound that
inhibits the active site of an enzyme crucial to viral reproduction.
Drugmakers can also combine old-fashioned screening methods with
the newer methods based on structures.
Advanced approaches to drug discovery have generated ideas for
thwarting viruses at all stages of their life cycles. Viral species vary
in the fine details of their reproductive strategies. In general, though,
the stages of viral replication include attachment to the cells of a
host, release of viral genes into the cells' interiors, replication of all
viral genes and proteins (with help from the cells'
own protein-making machinery), joining of the components into
hordes of viral particles, and escape of those particles to begin the
cycle again in other cells.
The ideal time to ambush a virus is in the earliest stage of an
infection, before it has had time to spread throughout the body and
cause symptoms. Vaccines prove their worth at that point, because
they prime a person's immune system to specifically destroy a
chosen disease-causing agent, or pathogen, almost as soon as it
enters the body. Historically vaccines have achieved this priming by
exposing a person to a killed or weakened version of the infectious
agent that cannot make enough copies of itself to cause disease.
So-called subunit vaccines are the most common alternative to these.
They contain mere fragments of a pathogen; fragments alone have
no way to produce an infection but, if selected carefully, can evoke a
protective immune respons |
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