Antiviral drugs are a class of medication used specifically for treating
viral infections. Like antibiotics, specific antivirals are used for specific viruses. Antiviral drugs are one class of
antimicrobials, a larger group which also includes antibiotic, antifungal and antiparasitic drugs. They are relatively harmless to the host, and therefore can be used to
treat infections. They should be distinguished from
viricides, which actively deactivate virus particles outside the body.
Most of the antivirals now available are designed to help deal with HIV; herpes viruses, best known for causing cold sores and genital herpes, but actually causing a wide range of
diseases; the hepatitis B and C viruses, which can
cause liver cancer; and influenza A and B
viruses. Researchers are now working to extend the range of antivirals to other families of pathogens.
The emergence of antivirals is the product of a greatly expanded knowledge of the genetic and molecular function of organisms,
allowing biomedical researchers to understand the structure and function of viruses, major advances in the techniques for finding
new drugs, and the intense pressure placed on the medical profession to deal with the human immunodeficiency virus
(HIV), the cause of the deadly acquired immunodeficiency syndrome (AIDS) pandemic.
Almost all anti-microbials, including anti-virals, are subject to drug resistance as
the pathogens evolve to survive exposure to the treatment. As of 2007, only smallpox has been
successfully eradicated, and Poliomyelitis eradication is still underway. Both
of these efforts are using vaccines.
History
Modern medical science and practice has an array of effective tools, ranging from antiseptics to vaccines and antibiotics.
One field in which medicine has historically been weak, however, is in finding drugs to deal with viral infections. Highly effective vaccines have been recently developed to prevent such diseases, but
formerly, when someone contracted a virus, there was little that could be done but to recommend rest and plenty of fluids until
the disease ran its course.
The first experimental antivirals were developed in the 1960s, mostly to deal with herpesviruses, and were found using traditional trial-and-error
drug discovery methods. Researchers grew cultures of cells and infected them with the target virus. They then introduced
chemicals into the cultures they thought were likely to inhibit viral activity, and observed whether the level of virus in the
cultures rose or fell. Chemicals that seemed to have an effect were selected for closer study.
This was a very time-consuming, hit-or-miss procedure, and in the absence of a good knowledge of how the target virus worked,
it was not efficient in discovering antivirals that were effective and had few side effects.
It was not until the 1980s, when the full genetic sequences of viruses began to be
unraveled, that researchers began to learn how viruses worked in detail, and exactly what chemicals were needed to thwart their
reproductive cycle. Dozens of antiviral treatments are now available, and medical research is rapidly exploiting new knowledge
and technology to develop more.
Virus life cycle
Viruses consist of a genome and sometimes a few
enzymes stored in a capsule made of protein, and sometimes
covered with a lipid layer. Viruses cannot reproduce on their own, so they propagate by
subjugating a host cell to produce copies of themselves, thus producing the next generation.
Researchers working on such "rational drug design" strategies for developing antivirals
have tried to attack viruses at every stage of their life cycles. Viral life cycles vary in their precise details depending on
the species of virus, but they all share a general pattern:
- Attachment to a host cell.
- Release of viral genes and possibly enzymes into the host cell.
- Replication of viral components using host-cell machinery.
- Assembly of viral components into complete viral particles.
- Release of viral particles to infect new host cells.
Inadequacy of vaccines
Vaccines attack viruses when they are in the "complete particle" stage, outside of the
organism's cells. They traditionally consist of a weakened or killed version of a pathogen,
though more recently "subunit" vaccines have been devised that consist strictly of protein targets from the pathogen. They
stimulate the immune system without doing serious harm to the host, and so when the real
pathogen attacks the subject, the immune system responds to it quickly and blocks it.
Vaccines are very effective on stable viruses, but are of limited use in treating a patient who has already been infected.
They are also difficult to successfully deploy against rapidly mutating viruses, such as influenza (the vaccine for which is updated every year) and HIV. These two gaps
are where antiviral drugs become useful.
Anti-viral targeting technique
The general idea behind modern antiviral drug design is to identify viral proteins, or parts of proteins, that can be
disabled. These "targets" should generally be as unlike any proteins or parts of proteins in humans as possible, to reduce the
likelihood of side effects. The targets should also be common across many strains of a virus, or even among different species of
virus in the same family, so a single drug will have broad effectiveness. For example, a researcher might target a critical
enzyme synthesized by the virus, but not the patient, that is common across strains, and see what can be done to interfere with
its operation.
Once targets are identified, candidate drugs can be selected, either from drugs already known to have appropriate effects, or
by actually designing the candidate at the molecular level with a computer-aided
design program.
The target proteins can be manufactured in the lab for testing with candidate treatments by inserting the gene that synthesizes the target protein into bacteria or other kinds of cells. The cells are then cultured for mass production of the protein, which can
then be exposed to various treatment candidates and evaluated with "rapid screening" technologies.
Approaches by life cycle stage
Before cell entry
One anti-viral strategy is to interfere with the ability of a virus to infiltrate a target cell. The virus must go through a
sequence of steps to do this, beginning with binding to a specific "receptor"
molecule on the surface of the host cell and ending with the virus "uncoating" inside the cell and releasing its contents.
Viruses that have a lipid envelope must also fuse their envelope with the target cell, or with a vesicle that transports them
into the cell, before they can uncoat.
This stage of viral replication can be inhibited in two ways: 1. Using agents which mimic the virus-associated protein (VAP)
and bind to the cellular receptors. This may include VAP anti-idiotypic antibodies, anti-receptor antibodies, and natural ligands of the receptor and
anti-receptor antibodies.[clarify] 2. Using agents which mimic the receptor and bind to the VAP. This includes
anti-VAP antibodies, receptor anti-idiotypic antibodies, extraneous receptor and synthetic
receptor mimics.
This strategy of designing drugs can be very expensive, and since the process of generating anti-idiotypic antibodies is
partly trial and error, it can be a relatively slow process until an adequate molecule is produced.
A very early stage of viral infection is viral entry, when the virus attaches to and
enters the host cell. A number of "entry-inhibiting" or "entry-blocking" drugs are being developed to fight HIV. HIV most heavily
targets the immune-system white blood cells known as "helper T cells", and identifies these target cells through T-cell surface
receptors designated "CD4" and "CCR5". Attempts to interfere with the
binding of HIV with the CD4 receptor have failed to stop HIV from infecting helper T cells, but research continues on trying to
interfere with the binding of HIV to the CCR5 receptor in hopes that it will be more effective.
However, two entry-blockers, amantadine and rimantadine, have been introduced to combat influenza, and researchers are working on entry-inhibiting drugs
to combat hepatitis B and C virus.
One entry-blocker is pleconaril. Pleconaril works against rhinoviruses, which cause the common cold, by blocking a pocket on the
surface of the virus that controls the uncoating process. This pocket is similar in most strains of rhinoviruses and
enteroviruses, which can cause diarrhea, meningitis,
conjunctivitis, and encephalitis.
During viral synthesis
A second approach is to target the processes that synthesize virus components after a virus invades a cell. One way of doing
this is to develop nucleotide or nucleoside analogues
that look like the building blocks of RNA or DNA, but deactivate the
enzymes that synthesize the RNA or DNA once the analogue is incorporated.
The first successful antiviral, aciclovir, is a nucleoside analogue, and is effective
against herpesvirus infections. The first antiviral drug to be approved for treating HIV, zidovudine (AZT), is also a nucleoside analogue.
An improved knowledge of the action of reverse transcriptase has led to better nucleoside analogues to treat HIV infections.
One of these drugs, lamivudine, has been approved to treat hepatitis B, which uses reverse
transcriptase as part of its replication process. Researchers have gone further and developed inhibitors that do not look like
nucleosides, but can still block reverse transcriptase.
Other targets being considered for HIV antivirals include RNase H, which is a component of
reverse transcriptase that splits the synthesized DNA from the original viral RNA; and integrase, which splices the synthesized DNA into the host cell genome.
Once a virus genome becomes operational in a host cell, it then generates messenger RNA
(mRNA) molecules that direct the synthesis of viral proteins. Production of mRNA is initiated by proteins known as
transcription factors. Several antivirals are now being designed to block
attachment of transcription factors to viral DNA.
Genomics has not only helped find targets for many antivirals, it has provided the basis for an entirely new type of drug,
based on "antisense" molecules. These are segments of DNA or RNA that are designed as "mirror images" to critical sections of
viral genomes, and the binding of these antisense segments to these target sections blocks the operation of those genomes. A
phosphorothioate antisense drug named fomivirsen has been introduced, used to treat
opportunistic eye infections in AIDS patients caused by cytomegalovirus, and other
antisense antivirals are in development. An antisense structural type that has proven especially valuable in research is
Morpholino antisense. Morpholino oligos have been used to experimentally suppress many viral
types including caliciviruses [1], flaviviruses (including WNV [2] , Dengue [3] and HCV [4] ), and coronaviruses [5] and are currently in clinical development.
Yet another antiviral technique inspired by genomics is a set of drugs based on ribozymes,
which are enzymes that will cut apart viral RNA or DNA at selected sites. In their natural course, ribozymes are used as part of
the viral manufacturing sequence, but these synthetic ribozymes are designed to cut RNA and DNA at sites that will disable
them.
A ribozyme antiviral to deal with hepatitis C is in field testing, and ribozyme antivirals are being developed to deal with
HIV. An interesting variation of this idea is the use of genetically modified cells that can produce custom-tailored ribozymes.
This is part of a broader effort to create genetically modified cells that can be injected into a host to attack pathogens by
generating specialized proteins that block viral replication at various phases of the viral life cycle.
Some viruses include an enzyme known as a protease that cuts viral protein chains apart so
they can be assembled into their final configuration. HIV includes a protease, and so considerable research has been performed to
find "protease inhibitors" to attack HIV at that phase of its life-cycle. Protease inhibitors became available in the 1990s and
have proven effective, though they can have unusual side-effects, for example causing fat to build up in unusual places. Improved
protease inhibitors are now in development.
Release phase
The final stage in the life cycle of a virus is the release of completed viruses from the host cell, and this step has also
been targeted by antiviral drug developers. Two drugs named zanamivir (Relenza) and
oseltamivir (Tamiflu) that have been recently introduced to treat influenza prevent the
release of viral particles by blocking a molecule named neuraminidase that is found on the
surface of flu viruses, and also seems to be constant across a wide range of flu strains.
Immune system stimulation
A second category of tactics for fighting viruses involves encouraging the body's immune system to attack them, rather than
attacking them directly. Some antivirals of this sort do not focus on a specific pathogen, instead stimulating the immune system
to attack a range of pathogens.
One of the best-known of this class of drugs are interferons, which inhibit viral
synthesis in infected cells. One form of human interferon named "interferon alpha" is well-established as a treatment for
hepatitis B and C, and other interferons are also being investigated as treatments for various diseases.
A more specific approach is to synthesize antibodies, protein molecules that can bind to a
pathogen and mark it for attack by other elements of the immune system. Once researchers identify a particular target on the
pathogen, they can synthesize quantities of identical "monoclonal" antibodies to link up that target. A monoclonal drug is now
being sold to help fight respiratory syncytial virus in babies, and
another is being tested as a treatment for hepatitis B.
Examination of the genomes of viruses and comparison with the human genome show that some generate proteins that mimic those
used by the human immune system, confusing the immune-system response. Researchers are now searching for antivirals that can
recognize these intruder proteins and disable them.
See also
References
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