Antiviral drug
Encyclopedia
Antiviral drugs are a class of medication
used specifically for treating viral
infection
s. Like antibiotic
s for bacteria
, specific antivirals are used for specific viruses. Unlike most antibiotics, antiviral drugs do not destroy their target pathogen; instead they inhibit their development.
Antiviral drugs are one class of antimicrobial
s, 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
infection
s. They should be distinguished from viricides, which are not medication but deactivate or destroy virus particles, either inside or outside the body. Many common plants such as St John's wort are also widely believed in naturopathic circles to be viricides, but evidence to support this is far from sufficient in scientific circles. Antivirals also can be found in essential oils of some herbs, such as eucalyptus oil
and its
constituents.
Most of the antiviral drugs 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 working to extend the range of antivirals to other families of pathogens.
Designing safe and effective antiviral drugs is difficult, because viruses use the host's cells to replicate. This makes it difficult to find targets for the drug that would interfere with the virus without also harming the host organism's cells. Moreover, the major difficulty in developing vaccines and anti-viral drugs is due to viral variation.
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
.
s to vaccine
s and antibiotic
s, but no drugs to treat viral
infections. While vaccines proved effective in preventing many viral diseases, they could not help once a viral infection set in. Prior to the development of antivirals, when someone contracted a virus, there was little that could be done other than treating the symptoms
and waiting for the disease to run its course.
The first experimental antivirals were developed in the 1960s, mostly to deal with herpes viruses
, 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 into the cultures chemicals which they thought might 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 effective antivirals which had few side effect
s. Only in the 1980s, when the full genetic sequences of viruses began to be unraveled, did 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 available, and medical research is rapidly exploiting new knowledge and technology to develop more.
. Since animal cells do not regularly produce long dsRNA, the process selectively affected infected cells. The team named the process "Double-stranded RNA Activated Capase Oligomerizer" (DRACO). According to the lead researcher "In theory, [DRACO] should work against all viruses."
es consist of a genome
and sometimes a few enzyme
s stored in a capsule made of protein
(called a capsid
), and sometimes covered with a lipid
layer (sometimes called an 'envelope'). Viruses cannot reproduce on their own, and instead 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. Some species of mushrooms have been found to contain multiple antiviral chemicals with similar synergistic effects.
Viral life cycles vary in their precise details depending on the species of virus, but they all share a general pattern:
s bolster the body's immune system to better attack viruses in the "complete particle" stage, outside of the organism's cells. They traditionally consist of an attenuated (weakened or killed) version of the virus. These vaccines can, in rare cases, harm the host by inadvertently infecting the host with a full-blown viral occupancy. 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. In either case, 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
. Antiviral drugs are particularly useful in these cases.
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.
This stage of viral replication can be inhibited in two ways:
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.
, 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's 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.
Amantadine
and rimantadine
, have been introduced to combat influenza. These agents act on penetration/uncoating.
Pleconaril works against rhinovirus
es, 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 enterovirus
es, which can cause diarrhea, meningitis
, conjunctivitis
, and encephalitis
.
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. This approach is more commonly associated with the inhibition of reverse transcriptase
(RNA to DNA) than with "normal" transcriptase (DNA to RNA).
The first successful antiviral, acyclovir, 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.
Another target 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 .
, which splices the synthesized DNA into the host cell genome.
(mRNA) molecules that direct the synthesis of viral proteins. Production of mRNA is initiated by proteins known as transcription factor
s. Several antivirals are now being designed to block attachment of transcription factors to viral DNA.
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:
s, 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
has been suggested, 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.
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.
Protease inhibitors have also been seen in nature. A protease inhibitor was isolated from the Shiitake
mushroom (Lentinus edodes). The presence of this may explain the Shiitake mushrooms noted antiviral activity in vitro.
(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.
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 part of the standard 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 antibodies purified from infected individuals are also used as a treatment for hepatitis B.
as the pathogen
s mutate over time, becoming less susceptible to the treatment. For instance, a recent study published in Nature Biotechnology
emphasized the urgent need for augmentation of oseltamivir
(Tamiflu) stockpiles with additional antiviral drugs including zanamivir (Relenza) based on an evaluation of the performance of these drugs in the scenario that the 2009 H1N1 'Swine Flu' neuraminidase (NA) were to acquire the tamiflu-resistance (His274Tyr) mutation which is currently widespread in seasonal H1N1 strains.
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
used specifically for treating viral
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
s. Like antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
s for bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
, specific antivirals are used for specific viruses. Unlike most antibiotics, antiviral drugs do not destroy their target pathogen; instead they inhibit their development.
Antiviral drugs are one class of antimicrobial
Antimicrobial
An anti-microbial is a substance that kills or inhibits the growth of microorganisms such as bacteria, fungi, or protozoans. Antimicrobial drugs either kill microbes or prevent the growth of microbes...
s, a larger group which also includes antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
, antifungal
Antifungal drug
An antifungal medication is a medication used to treat fungal infections such as athlete's foot, ringworm, candidiasis , serious systemic infections such as cryptococcal meningitis, and others...
and antiparasitic drugs. They are relatively harmless to the host, and therefore can be used to treat
Pharmacotherapy
Pharmacotherapy is the treatment of disease through the administration of drugs. As such, it is considered part of the larger category of therapy....
infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
s. They should be distinguished from viricides, which are not medication but deactivate or destroy virus particles, either inside or outside the body. Many common plants such as St John's wort are also widely believed in naturopathic circles to be viricides, but evidence to support this is far from sufficient in scientific circles. Antivirals also can be found in essential oils of some herbs, such as eucalyptus oil
Eucalyptus oil
Eucalyptus oil is the generic name for distilled oil from the leaf of Eucalyptus, a genus of the plant family Myrtaceae native to Australia and cultivated worldwide. Eucalyptus oil has a history of wide application, as a pharmaceutical, antiseptic, repellent, flavouring, fragrance and industrial uses...
and its
constituents.
Most of the antiviral drugs now available are designed to help deal with HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
, herpes viruses
Herpesviridae
The Herpesviridae are a large family of DNA viruses that cause diseases in animals, including humans. The members of this family are also known as herpesviruses. The family name is derived from the Greek word herpein , referring to the latent, recurring infections typical of this group of viruses...
(best known for causing cold sores and genital herpes, but actually causing a wide range of diseases), the hepatitis B and C
Hepatitis C
Hepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...
viruses, which can cause liver cancer, and influenza A
Influenzavirus A
Influenza A virus causes influenza in birds and some mammals and is the only species of Influenzavirus A. Influenzavirus A is a genus of the Orthomyxoviridae family of viruses. Strains of all subtypes of influenza A virus have been isolated from wild birds, although disease is uncommon...
and B
Influenzavirus B
Influenzavirus B is a genus in the virus family Orthomyxoviridae. The only species in this genus is called "Influenza B virus".Influenza B viruses are only known to infect humans and seals, giving them influenza...
viruses. Researchers are working to extend the range of antivirals to other families of pathogens.
Designing safe and effective antiviral drugs is difficult, because viruses use the host's cells to replicate. This makes it difficult to find targets for the drug that would interfere with the virus without also harming the host organism's cells. Moreover, the major difficulty in developing vaccines and anti-viral drugs is due to viral variation.
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
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
) pandemic
Pandemic
A pandemic is an epidemic of infectious disease that is spreading through human populations across a large region; for instance multiple continents, or even worldwide. A widespread endemic disease that is stable in terms of how many people are getting sick from it is not a pandemic...
.
History
Through the mid- to late-20th century, medical science and practice included an array of effective tools, ranging from antisepticAntiseptic
Antiseptics are antimicrobial substances that are applied to living tissue/skin to reduce the possibility of infection, sepsis, or putrefaction...
s to vaccine
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...
s and antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
s, but no drugs to treat viral
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
infections. While vaccines proved effective in preventing many viral diseases, they could not help once a viral infection set in. Prior to the development of antivirals, when someone contracted a virus, there was little that could be done other than treating the symptoms
Symptomatic treatment
Symptomatic treatment is any medical therapy of a disease that only affects its symptoms, not its cause, i.e., its etiology. It is usually aimed at reducing the signs and symptoms for the comfort and well-being of the patient, but it also may be useful in reducing organic consequences and sequelae...
and waiting for the disease to run its course.
The first experimental antivirals were developed in the 1960s, mostly to deal with herpes viruses
Herpes simplex virus
Herpes simplex virus 1 and 2 , also known as Human herpes virus 1 and 2 , are two members of the herpes virus family, Herpesviridae, that infect humans. Both HSV-1 and HSV-2 are ubiquitous and contagious...
, 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 into the cultures chemicals which they thought might 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 effective antivirals which had few side effect
Adverse effect
In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
s. Only in the 1980s, when the full genetic sequences of viruses began to be unraveled, did 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 available, and medical research is rapidly exploiting new knowledge and technology to develop more.
Research
On 10-August-2011 researchers at MIT announced the publication of a new method of inhibiting viral infections in animal cells. The novel antiviral method involved intercepting and destroying Double-stranded Ribonucleic Acid (dsRNA) inside infected cells while ordering the cell to begin apoptosisApoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. Since animal cells do not regularly produce long dsRNA, the process selectively affected infected cells. The team named the process "Double-stranded RNA Activated Capase Oligomerizer" (DRACO). According to the lead researcher "In theory, [DRACO] should work against all viruses."
Virus life cycle
VirusVirus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
es consist of a genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
and sometimes a few enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s stored in a capsule made of protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
(called a capsid
Capsid
A capsid is the protein shell of a virus. It consists of several oligomeric structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may not correspond to individual proteins, are called capsomeres. The capsid encloses the genetic...
), and sometimes covered with a lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
layer (sometimes called an 'envelope'). Viruses cannot reproduce on their own, and instead 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. Some species of mushrooms have been found to contain multiple antiviral chemicals with similar synergistic effects.
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.
Limitations of vaccines
VaccineVaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...
s bolster the body's immune system to better attack viruses in the "complete particle" stage, outside of the organism's cells. They traditionally consist of an attenuated (weakened or killed) version of the virus. These vaccines can, in rare cases, harm the host by inadvertently infecting the host with a full-blown viral occupancy. Recently "subunit" vaccines have been devised that consist strictly of protein targets from the pathogen. They stimulate the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
without doing serious harm to the host. In either case, 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
Influenza
Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...
(the vaccine for which is updated every year) and HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
. Antiviral drugs are particularly useful in these cases.
Anti-viral targeting
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
Computer-aided design
Computer-aided design , also known as computer-aided design and drafting , is the use of computer technology for the process of design and design-documentation. Computer Aided Drafting describes the process of drafting with a computer...
program.
The target proteins can be manufactured in the lab for testing with candidate treatments by inserting the gene
Genetic engineering
Genetic engineering, also called genetic modification, is the direct human manipulation of an organism's genome using modern DNA technology. It involves the introduction of foreign DNA or synthetic genes into the organism of interest...
that synthesizes the target protein into bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
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.
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-idiotypicAnti-idiotypicAnti-idiotypic vaccines comprise antibodies that have three-dimensional immunogenic regions, designated idiotopes, that consist of protein sequences that bind to cell receptors...
antibodies, natural ligandLigandIn coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
s of the receptor and anti-receptor antibodies. - 2. Using agents which mimic the cellular receptor and bind to the VAP. This includes anti-VAP antibodiesAntibodyAn antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
, 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.
Entry inhibitor
A very early stage of viral infection is viral entryViral entry
Viral entry is the earliest stage of infection in the viral life cycle, as the virus comes into contact with the host cell and introduces viral material into the cell. The major steps involved in viral entry are shown below. Despite the variation among viruses, the generalities are quite similar...
, 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's white blood cells known as "helper T cells", and identifies these target cells through T-cell surface receptors designated "CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
" and "CCR5
CCR5
C-C chemokine receptor type 5, also known as CCR5, is a protein that in humans is encoded by the CCR5 gene. CCR5 is a member of the beta chemokine receptors family of integral membrane proteins...
". 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.
Uncoating inhibitor
Inhibitors of uncoating have also been investigated.Amantadine
Amantadine
Amantadine is the organic compound known formally as 1-adamantylamine or 1-aminoadamantane. The molecule consists of adamantane backbone that has an amino group substituted at one of the four methyne positions. This pharmaceutical is sold under the name Symmetrel for use both as an antiviral and an...
and rimantadine
Rimantadine
Rimantadine is an orally administered antiviral drug used to treat, and in rare cases prevent, influenzavirus A infection. When taken within one to two days of developing symptoms, rimantadine can shorten the duration and moderate the severity of influenza. Both rimantadine and the similar drug...
, have been introduced to combat influenza. These agents act on penetration/uncoating.
Pleconaril works against rhinovirus
Rhinovirus
Human rhinoviruses are the most common viral infective agents in humans and are the predominant cause of the common cold. Rhinovirus infection proliferates in temperatures between 33–35 °C , and this may be why it occurs primarily in the nose...
es, which cause the common cold
Common cold
The common cold is a viral infectious disease of the upper respiratory system, caused primarily by rhinoviruses and coronaviruses. Common symptoms include a cough, sore throat, runny nose, and fever...
, 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 enterovirus
Enterovirus
Enteroviruses are a genus of ssRNA viruses associated with several human and mammalian diseases. Serologic studies have distinguished 66 human enterovirus serotypes on the basis of antibody neutralization tests. Additional antigenic variants have been defined within several of the serotypes on the...
es, which can cause diarrhea, meningitis
Meningitis
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...
, conjunctivitis
Conjunctivitis
Conjunctivitis refers to inflammation of the conjunctiva...
, and encephalitis
Encephalitis
Encephalitis is an acute inflammation of the brain. Encephalitis with meningitis is known as meningoencephalitis. Symptoms include headache, fever, confusion, drowsiness, and fatigue...
.
During viral synthesis
A second approach is to target the processes that synthesize virus components after a virus invades a cell.Reverse transcription
One way of doing this is to develop nucleotideNucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
or nucleoside
Nucleoside
Nucleosides are glycosylamines consisting of a nucleobase bound to a ribose or deoxyribose sugar via a beta-glycosidic linkage...
analogues that look like the building blocks of RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
or DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, but deactivate the enzymes that synthesize the RNA or DNA once the analogue is incorporated. This approach is more commonly associated with the inhibition of reverse transcriptase
Reverse transcriptase
In the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
(RNA to DNA) than with "normal" transcriptase (DNA to RNA).
The first successful antiviral, acyclovir, is a nucleoside analogue, and is effective against herpesvirus infections. The first antiviral drug to be approved for treating HIV, zidovudine
Zidovudine
Zidovudine or azidothymidine is a nucleoside analog reverse-transcriptase inhibitor , a type of antiretroviral drug used for the treatment of HIV/AIDS. It is an analog of thymidine....
(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
Lamivudine
Lamivudine is a potent nucleoside analog reverse transcriptase inhibitor .It is marketed by GlaxoSmithKline with the brand names Zeffix, Heptovir, Epivir, and Epivir-HBV.Lamivudine has been used for treatment of chronic hepatitis B at a lower dose than for treatment of HIV...
, 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.
Another target being considered for HIV antivirals include RNase H
RNase H
The enzyme RNase H is a non-specific endonuclease and catalyzes the cleavage of RNA via a hydrolytic mechanism. Members of the RNase H family can be found in nearly all organisms, from archaea to bacteria and eukaryota....
- which is a component of reverse transcriptase that splits the synthesized DNA from the original viral RNA .
Integrase
Another target is integraseIntegrase
Retroviral integrase is an enzyme produced by a retrovirus that enables its genetic material to be integrated into the DNA of the infected cell...
, which splices the synthesized DNA into the host cell genome.
Transcription
Once a virus genome becomes operational in a host cell, it then generates messenger RNAMessenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
(mRNA) molecules that direct the synthesis of viral proteins. Production of mRNA is initiated by proteins known as transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s. Several antivirals are now being designed to block attachment of transcription factors to viral DNA.
Translation / antisense
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 complementary molecule 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 fomivirsenFomivirsen
Fomivirsen is an antiviral drug. It is used in the treatment of cytomegalovirus retinitis in immunocompromised patients, including those with AIDS...
has been introduced, used to treat opportunistic eye infections in AIDS patients caused by cytomegalovirus
Cytomegalovirus
Cytomegalovirus is a viral genus of the viral group known as Herpesviridae or herpesviruses. It is typically abbreviated as CMV: The species that infects humans is commonly known as human CMV or human herpesvirus-5 , and is the most studied of all cytomegaloviruses...
, and other antisense antivirals are in development. An antisense structural type that has proven especially valuable in research is morpholino
Morpholino
In molecular biology, a Morpholino is a molecule in a particular structural family that is used to modify gene expression. Morpholino oligomers are an antisense technology used to block access of other molecules to specific sequences within nucleic acid...
antisense.
Morpholino oligos have been used to experimentally suppress many viral types:
- caliciviruses
- flavivirusFlavivirusFlavivirus is a genus of the family Flaviviridae. This genus includes the West Nile virus, dengue virus, tick-borne encephalitis virus, yellow fever virus, and several other viruses which may cause encephalitis....
es (including WNV)
- dengue
- HCVHepatitis C virusHepatitis C virus is a small , enveloped, positive-sense single-stranded RNA virus of the family Flaviviridae...
- coronavirusCoronavirusCoronaviruses are species in the genera of virus belonging to the subfamily Coronavirinae in the family Coronaviridae. Coronaviruses are enveloped viruses with a positive-sense single-stranded RNA genome and a helical symmetry. The genomic size of coronaviruses ranges from approximately 16 to 31...
es
Translation / ribozymes
Yet another antiviral technique inspired by genomics is a set of drugs based on ribozymeRibozyme
A ribozyme is an RNA molecule with a well defined tertiary structure that enables it to catalyze a chemical reaction. Ribozyme means ribonucleic acid enzyme. It may also be called an RNA enzyme or catalytic RNA. Many natural ribozymes catalyze either the hydrolysis of one of their own...
s, 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
Hepatitis C
Hepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...
has been suggested, 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.
Protease inhibitors
Some viruses include an enzyme known as a proteaseProtease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
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
Protease inhibitor (pharmacology)
Protease inhibitors are a class of drugs used to treat or prevent infection by viruses, including HIV and Hepatitis C. PIs prevent viral replication by inhibiting the activity of proteases, e.g.HIV-1 protease, enzymes used by the viruses to cleave nascent proteins for final assembly of new...
" 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.
Protease inhibitors have also been seen in nature. A protease inhibitor was isolated from the Shiitake
Shiitake
The Shiitake is an edible mushroom native to East Asia, which is cultivated and consumed in many Asian countries, as well as being dried and exported to many countries around the world. It is a feature of many Asian cuisines including Vietnamese, Chinese, Japanese, Korean and Thai...
mushroom (Lentinus edodes). The presence of this may explain the Shiitake mushrooms noted antiviral activity in vitro.
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 oseltamivirOseltamivir
Oseltamivir INN , an antiviral drug, slows the spread of influenza virus between cells in the body by stopping the virus from chemically cutting ties with its host cell; median time to symptom alleviation is reduced by 0.5–1 day. The drug is sold under the trade name Tamiflu, and is taken orally...
(Tamiflu) that have been recently introduced to treat influenza prevent the release of viral particles by blocking a molecule named neuraminidase
Neuraminidase
Neuraminidase enzymes are glycoside hydrolase enzymes that cleave the glycosidic linkages of neuraminic acids. Neuraminidase enzymes are a large family, found in a range of organisms. The most commonly known neuraminidase is the viral neuraminidase, a drug target for the prevention of the spread...
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 part of the standard 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 antibodies purified from infected individuals are also used as a treatment for hepatitis B.
Acquired resistance
Almost all anti-microbials, including anti-virals, are subject to drug resistanceDrug resistance
Drug resistance is the reduction in effectiveness of a drug such as an antimicrobial or an antineoplastic in curing a disease or condition. When the drug is not intended to kill or inhibit a pathogen, then the term is equivalent to dosage failure or drug tolerance. More commonly, the term is used...
as the pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
s mutate over time, becoming less susceptible to the treatment. For instance, a recent study published in Nature Biotechnology
Nature Biotechnology
Nature Biotechnology is an academic journal covering the science and business of biotechnology.Nature Biotechnology is a continuation of Bio/Technology , which was founded in 1983 and renamed in 1996. It is published monthly by the Nature Publishing Group, a division of Macmillan Publishers Ltd...
emphasized the urgent need for augmentation of oseltamivir
Oseltamivir
Oseltamivir INN , an antiviral drug, slows the spread of influenza virus between cells in the body by stopping the virus from chemically cutting ties with its host cell; median time to symptom alleviation is reduced by 0.5–1 day. The drug is sold under the trade name Tamiflu, and is taken orally...
(Tamiflu) stockpiles with additional antiviral drugs including zanamivir (Relenza) based on an evaluation of the performance of these drugs in the scenario that the 2009 H1N1 'Swine Flu' neuraminidase (NA) were to acquire the tamiflu-resistance (His274Tyr) mutation which is currently widespread in seasonal H1N1 strains.
See also
- List of antiviral drugs
- Antiretroviral drugAntiretroviral drugAntiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. When several such drugs, typically three or four, are taken in combination, the approach is known as Highly Active Antiretroviral Therapy, or HAART...
(especially HAART for HIV) - Discovery and development of CCR5 receptor antagonistsDiscovery and development of CCR5 receptor antagonistsCCR5 receptor antagonists are a class of small molecules that antagonize the CCR5 receptor. The C-C motif chemokine receptor CCR5 is involved in the HIV entry process...
(for HIV)