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16楼
发表于 2003-3-19 13:54
怎么内容不全了，是bug吗？我把后面没显示出的内容补上。
幸亏我有存底。
英文续
An early subunit vaccine, for hepatitis B, was made by isolating the
virus from the plasma (the fluid component of blood) of people who
were infected and then purifying the desired proteins. Today a
subunit hepatitis B vaccine is made by genetic engineering.
Scientists use the gene for a specific hepatitis B protein to
manufacture pure copies of the protein. Additional vaccines
developed with the help of genomics are in development for other
important viral diseases, among them dengue fever, genital herpes
and the often fatal hemorrhagic fever caused by the Ebola virus.
Several vaccines are being investigated for preventing or treating
HIV. But HIV's genes mutate rapidly, giving rise to many viral
strains; hence, a vaccine that induces a reaction against certain
strains might have no effect against others. By comparing the
genomes of the various HIV strains, researchers can find sequences
that are present in most of them and then use those sequences to
produce purified viral protein fragments. These can be tested for
their ability to induce immune protection against strains found
worldwide. Or vaccines might be tailored to the HIV variants
prominent in particular regions.
Bar Entry
Treatments become important when a vaccine is not available or not
effective. Antiviral treatments effect cures for some patients, but so
far most of them tend to reduce the severity or duration of a viral
infection. One group of therapies limits viral activity by interfering
with entry into a favored cell type.
The term "entry" actually covers a few steps, beginning with the
binding of the virus to some docking site, or receptor, on a host cell
and ending with "uncoating" inside the cell; during uncoating, the
protein capsule (capsid) breaks up, releasing the virus's genes. Entry
for enveloped viruses requires an extra step. Before uncoating can
occur, these microorganisms must fuse their envelope with the cell
membrane or with the membrane of a vesicle that draws the virus
into the cell's interior.
Several entry-inhibiting drugs in development attempt to block HIV
from penetrating cells. Close examination of the way HIV interacts
with its favorite hosts (white blood cells called helper T cells) has
indicated that it docks with molecules on those cells called CD4 and
CCR5. Although blocking CD4 has failed to prevent HIV from
entering cells, blocking CCR5 may yet do so.
Amantidine and rimantidine, the first two (of four) influenza drugs to
be introduced, interrupt other parts of the entry process.
Drugmakers found the compounds by screening likely chemicals for
their overall ability to interfere with viral replication, but they have
since learned more specifically that the compounds probably act by
inhibiting fusion and uncoating. Fusion inhibitors discovered with
the aid of genomic information are also being pursued against
respiratory syncytial virus (a cause of lung disease in infants born
prematurely),
hepatitis B and C, and HIV.
Many colds could soon be controlled by another entry blocker,
pleconaril, which is reportedly close to receiving federal approval.
Genomic and structural comparisons have shown that a pocket on
the surface of rhinoviruses (responsible for most colds) is similar in
most variants. Pleconaril binds to this pocket in a way that inhibits
the uncoating of the virus. The drug also appears to be active against
enteroviruses, which can cause diarrhea, meningitis, conjunctivitis
and encephalitis.
Jam the Copier
A number of antivirals on sale and under study operate after
uncoating, when the viral genome, which can take the form of DNA
or RNA, is freed for copying and directing the production of viral
proteins. Several of the agents that inhibit genome replication are
nucleoside or nucleotide analogues, which resemble the building
blocks of genes. The enzymes that copy viral DNA or RNA
incorporate these mimics into the nascent strands. Then the mimics
prevent the enzyme from adding any further building blocks,
effectively aborting viral replication.
Acyclovir, the earliest antiviral proved to be both effective and
relatively nontoxic, is a nucleoside analogue that was discovered by
screening selected compounds for their ability to interfere with the
replication of herpes simplex virus. It is prescribed mainly for genital
herpes, but chemical relatives have value against other herpesvirus
infections, such as shingles caused by varicella zoster and
inflammation of the retina caused by cytomegalovirus.
The first drug approved for use against HIV, zidovudine (AZT), is a
nucleoside analogue as well. Initially developed as an anticancer
drug, it was shown to interfere with the activity of reverse
transcriptase, an enzyme that HIV uses to copy its RNA genome into
DNA. If this copying step is successful, other HIV enzymes splice
the DNA into the chromosomes of an invaded cell, where the
integrated DNA directs viral reproduction.
AZT can cause severe side effects, such as anemia. But studies of
reverse transcriptase, informed by knowledge of the enzyme's gene
sequence, have enabled drug developers to introduce less toxic
nucleoside analogues. One of these, lamivudine, has also been
approved for hepatitis B, which uses reverse transcriptase to convert
RNA copies of its DNA genome back into DNA. Intense analyses of
HIV reverse transcriptase have led as well to improved versions of a
class of reverse transcriptase inhibitors that do not resemble
nucleosides.
Genomics has uncovered additional targets that could be hit to
interrupt replication of the HIV genome. Among these is RNase H, a
part of reverse transcriptase that separates freshly minted HIV DNA
from RNA. Another is the active site of integrase, an enzyme that
splices DNA into the chromosomal DNA of the infected cell. An
integrase inhibitor is now being tested in HIV-infected volunteers.
Impede Protein Production
All viruses must at some point in their life cycle transcribe genes
into mobile strands of messenger RNA, which the host cell then
"translates," or uses as a guide for making the encoded proteins.
Several drugs in development interfere with the transcription stage
by preventing proteins known as transcription factors from attaching
to viral DNA and switching on the production of messenger RNA.
Genomics helped to identify the targets for many of these agents. It
also made possible a novel kind of drug: the antisense molecule. If
genomic research shows that a particular protein is needed by a
virus, workers can halt the protein's production by masking part of
the corresponding RNA template with a custom-designed DNA
fragment able to bind firmly to the selected RNA sequence. An
antisense drug, fomivirsen, is already used to treat eye infections
caused by cytomegalovirus in AIDS patients. And antisense agents
are in development for other viral diseases; one of them blocks
production of the HIV protein Tat, which is needed for the
transcription of other HIV genes.
Drugmakers have also used their knowledge of viral genomes to
identify sites in viral RNA that are susceptible to cutting by
ribozymes--enzymatic forms of RNA. A ribozyme is being tested in
patients with hepatitis C, and ribozymes for HIV are in earlier stages
of development. Some such projects employ gene therapy:
specially designed genes are introduced into cells, which then
produce the needed ribozymes. Other types of HIV gene therapy
under study give rise to specialized antibodies that seek targets
inside infected cells or to other proteins that latch onto certain viral
gene sequences within those cells.
Some viruses produce a protein chain in a cell that must be spliced to
yield functional proteins. HIV is among them, and an enzyme known
as a protease performs this cutting. When analyses of the HIV
genome pinpointed this activity, scientists began to consider the
protease a drug target. With enormous help from computer-assisted
structure-based research, potent protease inhibitors became available
in the 1990s, and more are in development. The inhibitors that are
available so far can cause disturbing side effects, such as the
accumulation of fat in unusual places, but they nonetheless prolong
overall health and life in many people when taken in combination
with other HIV antivirals. A new generation of protease
inhibitors is in the research pipeline.
Stop Traffic
Even if viral genomes and proteins are reproduced in a cell, they will
be harmless unless they form new viral particles able to escape from
the cell and migrate to other cells. The most recent influenza drugs,
zanamivir and oseltamivir, act at this stage. A molecule called
neuraminidase, which is found on the surface of both major types of
influenza (A and B), has long been known to play a role in helping
viral particles escape from the cells that produced them. Genomic
comparisons revealed that the active site of neuraminidase is similar
among various influenza strains, and structural studies enabled
researchers to design compounds able to plug that site. The other flu
drugs act only against type A.
Drugs can prevent the cell-to-cell spread of viruses in a different
way--by augmenting a patient's immune responses. Some of these
responses are nonspecific: the drugs may restrain the spread through
the body of various kinds of invaders rather than homing in on a
particular pathogen. Molecules called interferons take part in this
type of immunity, inhibiting protein synthesis and other aspects of
viral replication in infected cells. For that reason, one form of human
interferon, interferon alpha, has been a mainstay of therapy for
hepatitis B and C. (For hepatitis C, it is used with an older drug,
ribavirin.) Other interferons are under study,
too.
More specific immune responses include the production of standard
antibodies, which recognize some fragment of a protein on the
surface of a viral invader, bind to that protein and mark the virus for
destruction by other parts of the immune system. Once researchers
have the gene sequence encoding a viral surface protein, they can
generate pure, or "monoclonal," antibodies to selected regions of the
protein. One monoclonal is on the market for preventing respiratory
syncytial virus in babies at risk for this infection; another is being
tested in patients suffering from hepatitis B.
Comparisons of viral and human genomes have suggested yet
another antiviral strategy. A number of viruses, it turns out, produce
proteins that resemble molecules involved in the immune response.
Moreover, certain of those viral mimics disrupt the immune
onslaught and thus help the virus to evade destruction. Drugs able to
intercept such evasion-enabling proteins may preserve full immune
responses and speed the organism's recovery from numerous viral
diseases. The hunt for such agents is under way.
The Resistance Demon
The pace of antiviral drug discovery is nothing short of breathtaking,
but at the same time, drugmakers have to confront a hard reality:
viruses are very likely to develop resistance, or insensitivity, to many
drugs. Resistance is especially probable when the compounds are
used for long periods, as they are in such chronic diseases as HIV
and in quite a few cases of hepatitis B and C. Indeed, for every HIV
drug in the present arsenal, some viral strain exists that is resistant to
it and, often, to additional drugs. This resistance stems from the
tendency of viruses--especially RNA viruses and most especially
HIV--to mutate rapidly. When a mutation enables a viral strain to
overcome some obstacle to reproduction (such as a drug), that strain
will thrive in the face of the obstacle. To keep the resistance demon
at bay until effective vaccines are found, pharmaceutical companies
will have to develop more drugs. When mutants resistant to a
particular drug arise, reading their genetic text can indicate where the
mutation lies in the viral genome and suggest how that mutation
might alter the interaction between the affected viral protein and the
drug. Armed with that information, researchers can begin
structure-based or other studies designed to keep the drug working
despite the mutation.
Pharmaceutical developers are also selecting novel drugs based on
their ability to combat viral strains that are resistant to other drugs.
Recently, for instance, DuPont Pharmaceuticals chose a new HIV
nonnucleoside reverse transcriptase inhibitor, DPC 083, for
development precisely because of its ability to overcome viral
resistance to such inhibitors. The company's researchers first
examined the mutations in the reverse transcriptase gene that
conferred resistance. Next they turned to computer modeling to find
drug designs likely to inhibit the reverse transcriptase enzyme in
spite of those mutations. Then, using genetic engineering, they
created viruses that produced the mutant enzymes and selected the
compound best able to limit reproduction by those viruses. The drug
is now being evaluated in HIV-infected patients.
It may be some time before virtually all serious viral infections are
either preventable by vaccines or treatable by some effective drug
therapy. But now that the sequence of the human genome is available
in draft form, drug designers will identify a number of previously
undiscovered proteins that stimulate the production of antiviral
antibodies or that energize other parts of the immune system against
viruses. I fully expect these discoveries to translate into yet more
antivirals. The insights gleaned from the human genome, viral
genomes and other advanced drug-discovery methods are sure to
provide a flood of needed antivirals
within the next 10 to 20 years.
--------------------------------------------------------------------------------
Further Information:
Viral Strategies of Immune Evasion. Hidde L. Ploegh in Science,
Vol. 280, No. 5361, pages 248-253; April
10, 1998.
Strategies for Antiviral Drug Discovery. Philip S. Jones in Antiviral
Chemistry and Chemotherapy, Vol. 9, No.
4, pages 283-302; July 1998.
New Technologies for Making Vaccines. Ronald W. Ellis in Vaccine,
Vol. 17, No. 13-14, pages
1596-1604; March 26, 1999.
Protein Design of an HIV-1 Entry Inhibitor. Michael J. Root,
Michael S. Kay and Peter S. Kim in Science, Vol.
291, No. 5505, pages 884-888; February 2, 2001.
Antiviral Chemotherapy: General Overview. Jack M. Bernstein,
Wright State University School of Medicine,
Division of Infectious Diseases, 2000. Available at
www.med.wright.edu/im/AntiviralChemotherapy.html
--------------------------------------------------------------------------------
The Author
WILLIAM A. HASELTINE, who has a doctorate in biophysics from
Harvard University, is the chairman of the board of directors and
chief executive officer of Human Genome Sciences; he is also editor
in chief of a new publication, the Journal of Regenerative Medicine,
and serves on the editorial boards of several other scientific journals.
He was a professor at the Dana-Farber Cancer Institute, an affiliate
of Harvard Medical School, and at the Harvard School of Public
Health from 1988 to 1995. His laboratory was the first to assemble
the sequence of the AIDS virus genome. Since 1981 he has helped
found more than 20 biotechnology companies.
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