Antiviral Drugs
Antiviral Drugs
History and Scientific Foundations
Introduction
Antiviral drugs are used to prevent or treat viral infections. They are antimicrobial compounds, as are anti-biotics. However, antiviral compounds do not have the same mode of action as antibiotics. This is because most antibiotics rely on the ability of the bacteria to grow and divide. Bacteria grow and divide independently. In contrast, viruses must infect a host cell before they can exploit the host cell's genetic machinery to manufacture the components of new virus particles. Antibiotics are useless against viruses, both because viruses are localized inside of another cell or tissue, and because viruses are not alive in the absence of the host cell.
Antibiotics and antiviral drugs are similar in that specific drugs are designed for specific targets. For example, anti-retroviral drugs specifically inhibit infections caused by retroviruses, such as the human immunodeficiency virus (HIV). Other antiviral drugs specifically target other viruses, including herpes viruses and the various hepatitis viruses.
History and Scientific Foundations
The history of antiviral compounds dates back only to the 1960s. Prior to that time, a viral illness had to run its course. In the 1960s, antiviral drugs were developed to deal with herpes infections (which include cold sores, genital infection, chickenpox, mononucleosis, and Kaposi's sarcoma). At that time, the development of the drugs was more a trial-and-error process than a directed process. The process typically involved growing cultures of a particular type of cell and then infecting the cells with a particular virus. Successful infection is often apparent by a change in the appearance of the host cell. By adding compounds during the infection, researchers could monitor whether the visible signs of infection occurred or not. The absence of changes in the host cells was an indication that the particular compound was a potential antiviral agent.
This process was tedious and time-consuming. Beginning in the 1970s, advances in molecular biology made antiviral drug design more focused. The genetic sequences of disease-causing viruses began to be determined. In addition, it was learned that many viruses initiated infection by recognizing and binding to sites on the surface of host cells. As the three-dimensional shapes of these host sites and the molecular details of the binding of the virus were clarified, it became possible to design compounds to block the binding.
The binding process can be blocked in two ways. In one approach, the target site on the host surface is occupied by an added molecule. Because the site is occupied, the virus is unable to bind to it. In the second approach, the viral recognition site is blocked by the addition of a molecule. The blocking molecule may be an antibody—a protein that is produced by the immune system—that has been produced in the laboratory. Then virus particles cannot gain access to the host cell; they are stranded outside the host cells and can be destroyed when they are recognized by the hosts’ immune system, which causes antiviral immune molecules to be made and deployed.
This strategy of blocking viral infection very early in the infectious process is the basis of some viral vaccines. It can be very successful if the host or viral target sites do not change. However, in viral infections such as influenza, the viral site can change from year to year. A vaccine designed for the viral strain that dominates one year may be ineffective the next year, which is why new influenza vaccines need to be produced and administered prior to each flu season.
Some antiviral drugs operate slightly differently, by blocking the uptake of virus into the host cell. Other antiviral drugs prevent the infecting virus from using the host cell's genetic replication (duplication) mechanisms. The numbers of infecting viruses are not reduced, but, because the infection process is blocked, new viruses are not made. Once again, the host's immune system can more easily deal with the stranded viruses.
Two antiviral drugs, idoxuridine and trifluridine, halt viral infection at the genetic level. These drugs act by replacing one of the units (a compound called thymidine) that forms the genetic material. The drugs are able to do this because their structure is similar to the structure of thymidine. The incorporation of either drug produces DNA that does not function. Other drugs mimic other compounds, and their incorporation produces the same result. However, the drugs can also be incorporated into the DNA of the host cells, which disrupts their function. This action can cause side effects, but if the infection is stopped it can be worthwhile in the longer term.
Other antiviral drugs, such as acyclovir, target an enzyme produced by the virus, usually early in the infection, that is vital for the replication of the genetic material. The drug binds to the enzyme, which prevents the enzyme from binding to its normal target. As a result, DNA formation stops. Acyclovir is used to treat infections due to herpes simplex viruses and Epstein-Barr virus.
Zidovudine (AZT) acts against HIV by blocking the activity of the reverse transcriptase enzyme. This enzyme makes it possible for the infecting virus to convert its RNA to DNA, and this DNA is subsequently used by the host cell's replication machinery to produce new viral constituents. The compound can become incorporated into the host cell DNA, which also blocks the replication of viral genetic material. AZT is beneficial in reducing the transmission of HIV from a pregnant woman to her developing fetus and to her newborn during labor or breastfeeding.
WORDS TO KNOW
ANTIBODY: Antibodies, or Y-shaped immunoglobulins, are proteins found in the blood that help to fight against foreign substances called antigens. Antigens, which are usually proteins or polysaccharides, stimulate the immune system to produce antibodies. The antibodies inactivate the antigen and help to remove it from the body. While antigens can be the source of infections from pathogenic bacteria and viruses, organic molecules detrimental to the body from internal or environmental sources also act as antigens. Genetic engineering and the use of various mutational mechanisms allow the construction of a vast array of antibodies (each with a unique genetic sequence).
ENZYME: Enzymes are molecules that act as critical catalysts in biological systems. Catalysts are substances that increase the rate of chemical reactions without being consumed in the reaction. Without enzymes, many reactions would require higher levels of energy and higher temperatures than exist in biological systems. Enzymes are proteins that possess specific binding sites for other molecules (substrates). A series of weak binding interactions allow enzymes to accelerate reaction rates. Enzyme kinetics is the study of enzymatic reactions and mechanisms. Enzyme inhibitor studies have allowed researchers to develop therapies for the treatment of diseases, including AIDS.
MESSENGER RIBONUCLEIC ACID (MRNA): A molecule of RNA that carries the genetic information for producing one or more proteins; mRNA is produced by copying one strand of DNA, but in eukaryotes is able to move from the nucleus to the cytoplasm (where protein synthesis takes place).
REPLICATION: A process of reproducing, duplicating, copying, or repeating something, such as the duplication of DNA or the recreation of characteristics of an infectious disease in a laboratory setting.
RESISTANCE: Immunity developed within a species (especially bacteria) via evolution to an antibiotic or other drug. For example, in bacteria, the acquisition of genetic mutations that render the bacteria invulnerable to the action of antibiotics.
STRAIN: A subclass or a specific genetic variation of an organism.
Still other antiviral drugs focus on translation—the process whereby the messenger ribonucleic acid (mRNA) (which is formed from instructions encoded in DNA) is used to manufacture compounds, such as protein. Some antiviral drugs block mRNA formation and disrupt the translation process. Antiviral therapy also involves molecular tools. The best example is oligonucleotides, which are sequences of the building blocks of genetic material that are deliberately made to be complimentary to a target sequence of viral genetic material. The term complimentary means that the two sequences are able to chemically associate with one another. When the oligonucleotide binds to a stretch of viral genetic material, it prevents that stretch from being used in viral replication. One oligonucleotide-based drug is available for the treatment of eye infections in patients with acquired immunodeficiency syndrome (AIDS, also cited as acquired immune deficiency syndrome).
Applications and Research
The different mechanisms of action of different antiviral drugs have been useful in treating a variety of viral infections. For example, acyclovir, which was the first successful antiviral drug developed, is used to treat infections caused by herpes viruses, which include lesions on the genitals, in the mouth, and even in the brain, as well as treating chickenpox and shingles. The antiviral drug ganciclovir has been useful in the treatment of cytomegalovirus-mediated eye infections.
A well-known type of antiviral drug acts against retroviruses, in particular human HIV, the virus that causes AIDS. Most of the anti-retroviral drugs that have been developed have focused on combating HIV. The antiviral drug combination known as highly active anti-retroviral therapy (HAART) is targeted at blocking the use of the HIV RNA to manufacture DNA (which is then used to make the viral components); blocking the integration of viral genetic material into the host genome; and blocking adhesion of the virus to host cells. This multi-pronged approach can delay the progression of AIDS.
Research is progressing on antiviral drugs to block enzymes that cut DNA or RNA or proteins. These enzymes are important in the viral manufacturing process, and so their disruption can stop viral replication. Researchers are also exploring ways to block the release of an assembled virus from the host cell. If release can be blocked, new host cells cannot be infected and the infection stops.
Impacts and Issues
Antiviral drugs are invaluable in the treatment of viral diseases. Millions of people infected with HIV or suffering from the symptoms of AIDS utilize them. The U.S. National Institutes of Health recommends HAART even if symptoms are absent. HAART is expensive, however. This has limited its use to those who can afford it, either because of personal finances or government assistance. In the regions that are most affected by AIDS, such as sub-Saharan Africa, HAART is far less available. Economics deprive those most in need of help. Organizations, including the International Center for Research on Health, are working to introduce HAART more widely in Africa, and to encourage its use.
Anti-retroviral drugs, such as those used in HAART, are urgently needed in sub-Saharan Africa, where more than 25 million people are infected with HIV. It has been argued that widespread availability and use of anti-retroviral drugs could make AIDS in Africa a treatable (although still chronic) disease, similar to the situation in Europe, Australia, and North America. However, such a large-scale humanitarian effort may be unrealistic, given that private industry would likely bear most of the economic burden.
Despite this gloomy picture, some hope can be drawn from a 2003 pilot project by Médecins Sans Frontières, which demonstrated that anti-retroviral programs could be implemented in regions as poor as rural Africa. Furthermore, a United Nations summit held in 2005 produced a pledge from the leaders of the economically advantaged Group of Eight countries to make access to anti-retroviral drugs universal by 2010. However, many challenges remain to realize this ambitious goal.
Another issue involving antiviral drugs is the risks posed by their use. One example is the reverse transcriptase inhibitor, AZT. While the use of AZT has reduced maternal transmission of HIV, research published in 2007, which utilized animal models of the infection and also the genetic examination of humans, indicates that this benefit may be accompanied by a risk of cancer later in the infant's life. Fetuses exposed to AZT were found to display markedly more mutations in their genetic material than those not exposed to the drug. Since many cancers are associated with mutations, the research has highlighted a previously unrecognized risk of AZT therapy.
A second example concerns the antiviral drug oseltamivir phosphate (sold as Tamiflu®). The drug, which is used to combat viral influenza and which is approved for Americans one year of age and older, has recognized side effects. The most common (nausea and vomiting) are relatively inconsequential, but Tamiflu has been anecdotally linked to instances of abnormal mental behavior in teenagers in Japan and 84 adverse events in Canada, including the deaths of 10 elderly people. Health Canada is monitoring its use and is prepared to take more stringent action if warranted, in light of the possibility that a flu epidemic could result in the use of Tamiflu® by millions of people worldwide.
In 2006, Tamiflu® resistance was reported in several people infected with the H5N1 strain of the influenza virus. H5N1 is the cause of a serious and sometimes lethal form of flu called avian influenza (bird flu). Resistance to drugs is always a concern, since over time and with the increased use of the particular drug, the resistant strain becomes predominant in a population, making the disease much harder, and usually more expensive, to treat. Since Tamiflu® is available at pharmacies, the possibility that the drug might be used improperly or inappropriately increases the likelihood that such resistance will develop. Monitoring by the U.S. Centers for Disease Control and Prevention (CDC) did not detect the resistant strain in the U.S. during 2006. However, surveillance is ongoing, since the global range of H5N1 is growing, and because the evolving ability of the virus to be more easily transmitted from person to person makes the possibility of a global epidemic increasingly likely.
See AlsoDeveloping Nations and Drug Delivery; Pandemic Preparedness.
BIBLIOGRAPHY
Books
Driscoll, John S. Antiviral Drugs. New York: Wiley, 2005.
Torrence, Paul F. Antiviral Drug Discovery for Emerging Diseases and Bioterrorism Threats. New York: Wiley-Interscience, 2005.
Periodicals
Monto, Arnold S. “Vaccines and Antiviral Drugs in Pandemic Preparedness.” Emerging Infectious Diseases 12 (January 2006): 55–61.
Witt, Kristine L., et al. “Elevated Frequencies of Micronucleated Erythrocytes in Infants Exposed to Zidovudine in Utero and Postpartum to Prevent Mother-to-Child Transmission of HIV.” Environmental and Molecular Mutagenesis 48 (April-May 2007): 322–329.
Brian Hoyle