Antiviral drug
Antiviral drugs are a class of
Medical uses
Most of the antiviral drugs now available are designed to help deal with
Viruses use the host's cells to replicate and 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 antiviral drugs is due to viral variation.[7]
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 pressure placed on the medical profession to deal with the human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS).[8]
The first experimental antivirals were developed in the 1960s, mostly to deal with
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
Antiviral drug design
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Antiviral targeting
The general idea behind modern antiviral drug design is to identify viral proteins, or parts of proteins, that can be disabled.[11][13] These "targets" should generally be as unlike any proteins or parts of proteins in humans as possible, to reduce the likelihood of side effects and toxicity.[8] 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 by 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 virus life cycle stage
Viruses consist of a genome and sometimes a few enzymes 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 "
Viral life cycles vary in their precise details depending on the type 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.
Before cell entry
One antiviral 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 "
This stage of viral replication can be inhibited in two ways:
- Using agents which mimic the virus-associated protein (VAP) and bind to the cellular receptors. This may include VAP anti-idiotypic antibodies, natural ligands of the receptor and anti-receptor antibodies.[clarification needed]
- Using agents which mimic the cellular 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.
Entry inhibitor
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 a specific type of lymphocyte 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.
HIV infects a cell through fusion with the cell membrane, which requires two different cellular molecular participants, CD4 and a chemokine receptor (differing depending on the cell type). Approaches to blocking this virus/cell fusion have shown some promise in preventing entry of the virus into a cell. At least one of these entry inhibitors—a biomimetic peptide called Enfuvirtide, or the brand name Fuzeon—has received FDA approval and has been in use for some time. Potentially, one of the benefits from the use of an effective entry-blocking or entry-inhibiting agent is that it potentially may not only prevent the spread of the virus within an infected individual but also the spread from an infected to an uninfected individual.
One possible advantage of the therapeutic approach of blocking viral entry (as opposed to the currently dominant approach of viral enzyme inhibition) is that it may prove more difficult for the virus to develop resistance to this therapy than for the virus to mutate or evolve its enzymatic protocols.
Uncoating inhibitors
Inhibitors of uncoating have also been investigated.[16][17]
Amantadine and rimantadine have been introduced to combat influenza. These agents act on penetration and uncoating.[18]
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.[19]
Some scientists are making the case that a vaccine against rhinoviruses, the predominant cause of the common cold, is achievable. Vaccines that combine dozens of varieties of rhinovirus at once are effective in stimulating antiviral antibodies in mice and monkeys, researchers reported in Nature Communications in 2016.[20]
Rhinoviruses are the most common cause of the common cold; other viruses such as
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 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. 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, 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.
Another target being considered for HIV antivirals include
Integrase
Another target is integrase, which integrate the synthesized DNA into the host cell genome. Examples of integrase inhibitors include raltegravir, elvitegravir, and dolutegravir.
Transcription
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.
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 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:
- caliciviruses[23]
- flaviviruses (including West Nile virus)[24]
- dengue[25]
- HCV[26]
- coronaviruses[27]
Translation/ribozymes
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 has been suggested,[28] and ribozyme antivirals are being developed to deal with HIV.[29] 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.
Protein processing and targeting
Interference with post translational modifications or with targeting of viral proteins in the cell is also possible.[30]
Protease inhibitors
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.[31] 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.[32] 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).[33] The presence of this may explain the Shiitake mushrooms' noted antiviral activity in vitro.[34]
Long dsRNA helix targeting
Most viruses produce long
Assembly
Rifampicin acts at the assembly phase.[36]
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
Rather than attacking viruses directly, a second category of tactics for fighting viruses involves encouraging the body's immune system to attack them. 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.[37] One form of human interferon named "interferon alpha" is well-established as part of the standard treatment for hepatitis B and C,[38] and other interferons are also being investigated as treatments for various diseases.
A more specific approach is to synthesize
Antiviral drug resistance
The
The three FDA-approved neuraminidase antiviral flu drugs available in the United States, recommended by the CDC, include: oseltamivir (Tamiflu), zanamivir (Relenza), and peramivir (Rapivab).[41] Influenza antiviral resistance often results from changes occurring in neuraminidase and hemagglutinin proteins on the viral surface. Currently, neuraminidase inhibitors (NAIs) are the most frequently prescribed antivirals because they are effective against both influenza A and B. However, antiviral resistance is known to develop if mutations to the neuraminidase proteins prevent NAI binding.[43] This was seen in the H257Y mutation, which was responsible for oseltamivir resistance to H1N1 strains in 2009.[41] The inability of NA inhibitors to bind to the virus allowed this strain of virus with the resistance mutation to spread due to natural selection. Furthermore, a study published in 2009 in Nature Biotechnology emphasized the urgent need for augmentation of oseltamivir stockpiles with additional antiviral drugs including zanamivir. This finding was based on a performance evaluation of these drugs supposing the 2009 H1N1 'Swine Flu' neuraminidase (NA) were to acquire the oseltamivir-resistance (His274Tyr) mutation, which is currently widespread in seasonal H1N1 strains.[44]
Origin of antiviral resistance
The genetic makeup of viruses is constantly changing, which can cause a virus to become resistant to currently available treatments.[45] Viruses can become resistant through spontaneous or intermittent mechanisms throughout the course of an antiviral treatment.[41] Immunocompromised patients, more often than immunocompetent patients, hospitalized with pneumonia are at the highest risk of developing oseltamivir resistance during treatment.[41] Subsequent to exposure to someone else with the flu, those who received oseltamivir for "post-exposure prophylaxis" are also at higher risk of resistance.[46]
The mechanisms for antiviral resistance development depend on the type of virus in question. RNA viruses such as hepatitis C and influenza A have high error rates during genome replication because RNA polymerases lack proofreading activity.[47] RNA viruses also have small genome sizes that are typically less than 30 kb, which allow them to sustain a high frequency of mutations.[48] DNA viruses, such as HPV and herpesvirus, hijack host cell replication machinery, which gives them proofreading capabilities during replication. DNA viruses are therefore less error prone, are generally less diverse, and are more slowly evolving than RNA viruses.[47] In both cases, the likelihood of mutations is exacerbated by the speed with which viruses reproduce, which provides more opportunities for mutations to occur in successive replications. Billions of viruses are produced every day during the course of an infection, with each replication giving another chance for mutations that encode for resistance to occur.[49]
Multiple strains of one virus can be present in the body at one time, and some of these strains may contain mutations that cause antiviral resistance.[42] This effect, called the quasispecies model, results in immense variation in any given sample of virus, and gives the opportunity for natural selection to favor viral strains with the highest fitness every time the virus is spread to a new host.[50] Recombination, the joining of two different viral variants, and reassortment, the swapping of viral gene segments among viruses in the same cell, also play a role in resistance, especially in influenza.[48]
Antiviral resistance has been reported in antivirals for herpes, HIV, hepatitis B and C, and influenza, but antiviral resistance is a possibility for all viruses.[42] Mechanisms of antiviral resistance vary between virus types.[citation needed]
Detection of antiviral resistance
National and international surveillance is performed by the CDC to determine effectiveness of the current FDA-approved antiviral flu drugs.
Treatment options for antiviral resistant pathogens
If a virus is not fully wiped out during a regimen of antivirals, treatment creates a bottleneck in the viral population that selects for resistance, and there is a chance that a resistant strain may repopulate the host.[53] Viral treatment mechanisms must therefore account for the selection of resistant viruses.
The most commonly used method for treating resistant viruses is combination therapy, which uses multiple antivirals in one treatment regimen. This is thought to decrease the likelihood that one mutation could cause antiviral resistance, as the antivirals in the cocktail target different stages of the viral life cycle.[54] This is frequently used in retroviruses like HIV, but a number of studies have demonstrated its effectiveness against influenza A, as well.[55] Viruses can also be screened for resistance to drugs before treatment is started. This minimizes exposure to unnecessary antivirals and ensures that an effective medication is being used. This may improve patient outcomes and could help detect new resistance mutations during routine scanning for known mutants.[53] However, this has not been consistently implemented in treatment facilities at this time.
Vaccinations
The examples and perspective in this article deal primarily with the United States and do not represent a worldwide view of the subject. (February 2022) |
While most antivirals treat viral infection,
Vaccination policy
Vaccination controversy
Despite their successes, in the United States there exists plenty of stigma surrounding vaccines that cause people to be incompletely vaccinated. These "gaps" in vaccination result in unnecessary infection, death, and costs.[59] There are two major reasons for incomplete vaccination:
- Vaccines, like other medical treatments, have a risk of causing complications in some individuals (
- Low rates of vaccine-preventable disease, as a result of herd immunity, also make vaccines seem unnecessary and leave many unvaccinated.[63][64]
Although the American Academy of Pediatrics endorses universal immunization,[65] they note that physicians should respect parents' refusal to vaccinate their children after sufficient advising and provided the child does not face a significant risk of infection. Parents can also cite religious reasons to avoid public school vaccination mandates, but this reduces herd immunity and increases risk of viral infection.[57]
Limitations of vaccines
Vaccines boosts the body's immune system to better attack viruses in the "complete particle" stage, outside of the organism's cells. Traditional approaches to vaccine development include an attenuated (a live weakened) or inactivated (killed) version of the virus. Attenuated pathogens, in very rare cases, can revert to a pathogenic form. Inactivated vaccines have no possibility of introducing the disease they are given against; on the other hand, the immune response may not always occur or it may be short lived, requiring several doses. Recently, "subunit" vaccines have been devised containing only the antigenic parts of the pathogen. This makes the vaccine "more precise" but without guarantee that immunological memory will be formed in the correct manner.[66]
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.
Antiretroviral therapy as HIV prevention
Following the HPTN 052 study and PARTNER study, there is significant evidence to demonstrate that antiretroviral drugs inhibit transmission when the HIV virus in the person living with HIV has been undetectable for 6 months or longer.[67][68]
Public policy
Use and distribution
Guidelines regarding viral diagnoses and treatments change frequently and limit quality care.
Stockpiling
See also
- Antiretroviral drug(especially HAART for HIV)
- CRISPR-Cas13
- Discovery and development of CCR5 receptor antagonists(for HIV)
- Monoclonal antibody
- List of antiviral drugs
- Virucide
- Antiprion drugs and Astemizole
- Discovery and development of NS5A inhibitors
- COVID-19 drug repurposing research
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