Antiviral drug design 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 and toxicity. 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: • 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 "
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: • 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. • 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.
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 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 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. 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 molecules 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 •
flaviviruses (including
West Nile virus) •
dengue •
HCV •
coronaviruses
Translation/ribozymes Yet another antiviral technique inspired by genomics is a set of drugs based on
ribozymes, which are RNA sequences with catalytic activity 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 mushrooms' 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.
Classification of antivirals based on target Classifying antivirals based on their target of action, the protein or process that they interact with, serves to create two broad categories of antivirals: direct-acting antivirals (DAAs) and host-targeting antivirals (HTAs).
Direct-acting antivirals The term direct-acting antiviral (DAA) was first coined to describe anti-hepatitis C drugs that directly targeted viral processes. Prior antiviral regimens were designed to supplement the immune system’s ability to fight infection as a whole. In comparison, DAAs directly disrupt hepatitis C virus entry and replication processes by interfering with viral proteins. Prior to the discovery of DAAs, hepatitis C was treated with a combination of interferon and ribavirin which increase expression of genes involved in the antiviral immune response. DAAs drastically improved treatment outcomes by increasing safety and efficacy through increased specificity, resulting in increased sustained virological response (SVR) rates. SVR is achieved when hepatitis C virus
RNA remains undetectable 12–24 weeks after treatment ends. Once SVR is achieved, treatment is considered a success. Combination therapy of interferon and ribavirin has a SVR rate of approximately 65%. In contrast, SVR rates in clinical trials for numerous DAAs can be as high as 95%. and the antiviral prescribed depends on the strain (
genotypes) of hepatitis C virus that are causing the infection. Both during and at the end of treatment, blood tests are used to monitor the effectiveness of the treatment and subsequent cure. •
Harvoni (sofosbuvir and ledipasvir) •
Epclusa (sofosbuvir and velpatasvir) •
Vosevi (sofosbuvir, velpatasvir, and voxilaprevir) •
Zepatier (elbasvir and grazoprevir) •
Mavyret (glecaprevir and pibrentasvir) Despite its historical roots in hepatitis C research, the term "direct-acting antivirals" is currently used more broadly to describe all antiviral drugs with a viral protein as a target of action. Commonly used FDA-approved direct-acting antivirals include
aciclovir which is used to treat
herpes simplex virus, and
letermovir which is used to treat
cytomegalovirus. Aciclovir functions by competitively inhibiting viral DNA polymerase as well as inserting itself into the viral DNA chain terminating viral replication. Letermovir inhibits the viral DNA terminase complex that is responsible for cleaving viral DNA to be packaged into capsids. Both of these drugs bind to a specific viral protein, inhibiting the viral life cycle. DAAs have revolutionized treatment outcomes for hepatitis C and many other viral infections by improving treatment efficacy and reducing side effect profiles.
Host-targeting antivirals Unlike DAAs that target viral proteins, host targeting antivirals (HTAs) inhibit host proteins involved in viral infection and replication. HTAs are attractive to physicians because they have a higher genetic barrier to resistance than DAAs. Host genomes are generally more stable than viral genomes (particularly RNA viruses that are known for their high genetic instability and rapid mutation rate Interferon enhances the immune response by increasing the expression of genes involved in the antiviral immune response through activation of interferon receptors on the surface of the cell. Potential novel treatments including the
NMT inhibitor, has been shown to completely inhibit
Lassa (LAS) and
Junín (JUN)viral infections in cells based assays. Another host-directed antiviral acts on
EPRS1 which in turn acts, in human cells, as a proviral factor in mammarenaviruses infection, including
LCMV,
JUNV, and
LASV, and its inhibition using
halofuginon compound, a prolyl domain inhibitor of
EPRS1, completely abolishes the viral infection by interrupting viral assembly and budding. PKR has been shown to act as a proviral factor while the inhibition of its kinase activity restricted the virus replication and infectivity. ==Antiviral drug resistance==