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Most of the antivirals now available are designed to help deal with HIV, herpesvirus, which is best known for causing cold sores but actually covers a wide range of diseases, and the hepatitis B and C viruses, which can cause liver cancer. 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) epidemic. Though no one could sensibly claim that AIDS has been a benefit to humankind, it has certainly done much to advance the state of antiviral technology.
Contents |
History
Modern medical science and practice has something of an armory of effective tools, ranging from antiseptics and anesthetics to vaccines and antibiotics. One field in which medicine has been traditionally weak, however, is in finding drugs to deal with viral infections. To be sure, highly effective vaccines have been developed to prevent such diseases, but traditionally, once somebody came down sick with a virus, there was little that could be done but 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.
Since the mid-1980s, that scenario has changed dramatically. Dozens of antiviral treatments are now available, and most medical researchers feel we are only scratching at the surface of what can be done with these new drugs.
Development of antiviral drugs
Viruses, not quite proper living things, consist of a genome and sometimes a few enzymes (biocatalysts) stored in a capsule made of protein, and very rarely covered with a lipid (fat) layer. Viruses cannot reproduce on their own, and so they propagate by hijacking cells to do the job for them.
To develop early antivirals, researchers grew cultures of cells and infected them with the target virus. They then introduced chemicals into the cultures thought 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, not very good at discovering antivirals that were effective and had few side effects. It wasn't 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 kinds of molecules were needed to jam their machinery.
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.
In either case, the candidates can be synthesized by plugging the gene that synthesizes that protein into bacteria or other kinds of cells. The bacteria or cells are then cultured for mass production of the protein, which can then be sifted by "rapid screening" technologies to see which of the candidates are the most effective.
Antiviral drug design strategies
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.
The best time to attack a virus is as early as possible in its life cycle. In a sense, this is exactly what vaccines do. Vaccines 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 have an excellent track record for effectiveness, but they are of limited use in treating a patient who has already been infected. That's where antiviral drugs come in.
One approach is to interfere with the ability of a virus to get into a target cell. The virus has to take a sequence of actions 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 payload. 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. 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 drug can be very expensive. The process of generating anti-idiotypic antibodies is not fully understood. And it has very poor pharmacokinetics.
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 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.
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 jam 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 farther 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 the works. An antisense structual 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 devious 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 the natural order of things, 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 apart viral protein chains 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 odd side-effects, for example causing fat to build up in unusual places. Improved protease inhibitors are now in development.
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 and oseltamivir 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.
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 are devious, generating proteins that mimic those used by the human immune system, confusing the immune-system response. Researchers are now hunting for antivirals that can recognize these intruder proteins and disable them.
All drugs designed to fight pathogens have a common problem: over the long run, the pathogens evolve to acquire resistance to the drugs. This means that no antiviral will ever be a permanent solution. In fact, the structure of an antiviral compound will have to be tweaked as its target pathogen changes.
This is the nature of the game. However, antivirals are now promising to be the biggest innovation in pharmaceuticals since the introduction of antibiotics during the Second World War, and promise to be a major step forward in health care.
