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.
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 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 "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. Compounds isolated from fruiting bodies and filtrates of various mushrooms have broad-spectrum antiviral activities, but successful production and availability of such compounds as frontline antiviral is a long way away. Viral life cycles vary in their precise details depending on the type of virus, but they all share a general pattern:
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:
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 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.
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 inhibitor
Inhibitors of uncoating have also been investigated.
Amantadine and rimantadine have been introduced to combat influenza. These agents act on penetration and uncoating.
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.
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 have reported in Nature Communications in 2016.
Rhinoviruses are the most common cause of the common cold; other viruses such as respiratory syncytial virus, parainfluenza virus and adenoviruses can cause them too. Rhinoviruses also exacerbate asthma attacks. Although rhinoviruses come in many varieties, they do not drift to the same degree that influenza viruses do. A mixture of 50 inactivated rhinovirus types should be able to stimulate neutralizing antibodies against all of them to some degree.
During viral synthesis[edit]
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 RNase H—which is a component of reverse transcriptase that splits the synthesized DNA from the original viral RNA.
Integrase
Another target is integrase, which integrate the synthesized DNA into the host cell genome.
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:
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, 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.
Protein processing and targeting
Interference with post translational modifications or with targeting of viral proteins in the cell is also possible.
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.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 mushroom's noted antiviral activity in vitro.
Long dsRNA helix targeting
Most viruses produce long dsRNA helices during transcription and replication. In contrast, uninfected mammalian cells generally produce dsRNA helices of fewer than 24 base pairs during transcription. DRACO (double-stranded RNA activated caspase oligomerizer) is a group of experimental antiviral drugs initially developed at the Massachusetts Institute of Technology. In cell culture, DRACO was reported to have broad-spectrum efficacy against many infectious viruses, including dengue flavivirus, Amapari and Tacaribe arenavirus, Guama bunyavirus, H1N1 influenza and rhinovirus, and was additionally found effective against influenza in vivo in weanling mice. It was reported to induce rapid apoptosis selectively in virus-infected mammalian cells, while leaving uninfected cells unharmed. DRACO effects cell death via one of the last steps in the apoptosis pathway in which complexes containing intracellular apoptosis signalling molecules simultaneously bind multiple procaspases. The procaspases transactivate via cleavage, activate additional caspases in the cascade, and cleave a variety of cellular proteins, thereby killing the cell.
Assembly
Rifampicin acts at the assembly phase.
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.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.
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