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Encyclopedia > Antiviral drug

Antiviral drugs are a class of medication used specifically for treating viral infections. Like antibiotics, specific antivirals are used for specific viruses. Antiviral drugs are one class of antimicrobials, a larger group which also includes antibiotics, anti-fungal and anti-parasitic drugs. They are relatively harmless to the host, and therefore can be used to treat infections. They should be distingushed from viricides, which actively deactivate virus particles outside the body. A medication is a licenced drug taken to cure or reduce symptoms of an illness or medical condition. ... The human immunodeficiency virus (HIV) A virus is a submicroscopic parasite that infects cells in biological organisms. ... An infection is the detrimental colonization of a host organism by a foreign species. ... An antibiotic is a drug that kills or slows the growth of bacteria. ... An antimicrobial is a substance that kills or slows the growth of microbes like bacteria (antibacterial activity), fungi (antifungal activity), viruses (antiviral activity), or parasites (antiparasitic activity). ... An antibiotic is a drug that kills or slows the growth of bacteria. ... An antifungal drug is medication used to treat fungal infections such as athletes foot, ringworm and candidiasis (thrush), as well as serious systemic infections like cryptococcal meningitis. ... Therapy (in Greek: θεραπεία) or treatment is the attempted remediation of a health problem, usually following a diagnosis. ... An infection is the detrimental colonization of a host organism by a foreign species. ... A viricide is a chemical agent which kills viruses outside the body. ...


Most of the antivirals now available are designed to help deal with HIV; herpesvirus, which are best known for causing cold sores but actually cover a wide range of diseases; and the hepatitis B and C viruses, which can cause liver cancer. Researchers are now working to extend the range of antivirals to other families of pathogens. Genera Subfamily Alphaherpesvirinae    Simplexvirus    Varicellovirus    Mardivirus    Iltovirus Subfamily Betaherpesvirinae    Cytomegalovirus    Muromegalovirus    Roseolovirus Subfamily Gammaherpesvirinae    Lymphocryptovirus    Rhadinovirus Unassigned    Ictalurivirus The Herpesviridae are a family of DNA viruses that cause diseases in humans and animals. ... Hepatitis is a gastroenterological disease, featuring inflammation of the liver. ...


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) epidemic. Though no one could sensibly claim that AIDS has been a benefit to humankind, it has certainly done much to advance the state of antiviral technology. Human immunodeficiency virus, commonly known by the initialism HIV (original names HTLV-III and lymphadenopathy-associated virus), is a retrovirus that primarily infects vital components of the human immune system such as CD4+ T cells, macrophages and dendritic cells. ... Acquired immunodeficiency syndrome, or acquired immune deficiency syndrome (or acronym AIDS or Aids), is a collection of symptoms and infections resulting from the specific damage to the immune system caused by infection with the human immunodeficiency virus (HIV). ...

Contents


History

Modern medical science and practice has something of an armory of effective tools, ranging from antiseptics and anesthetics to vaccines and antibiotics. One field in which medicine has been traditionally weak, however, is in finding drugs to deal with viral infections. To be sure, highly effective vaccines have been developed to prevent such diseases, but traditionally, once somebody came down sick with a virus, there was little that could be done but recommend rest and plenty of fluids until the disease ran its course. An antiseptic (Greek αντι, against, and σηπτικος, putrefactive) is a substance that prevents the growth and reproduction of various microorganisms (such as bacteria, fungi, protozoa, and viruses) on the external surfaces of the body. ... Anesthesia (AE), also anaesthesia (BE), is the process of blocking the perception of pain and other sensations. ... A vaccine is an antigenic preparation used to produce active immunity to a disease, in order to prevent or ameliorate the effects of infection by any natural or wild strain of the organism. ... An antibiotic is a drug that kills or slows the growth of bacteria. ... The human immunodeficiency virus (HIV) A virus is a submicroscopic parasite that infects cells in biological organisms. ...


The first experimental antivirals were developed in the 1960s, mostly to deal with herpesviruses, and were found using traditional trial-and-error drug discovery methods. Trial and error is a method for obtaining knowledge, both propositional knowledge and know-how. ...


Since the mid-1980s, that scenario has changed dramatically. Dozens of antiviral treatments are now available, and most medical researchers feel we are only scratching at the surface of what can be done with these new drugs.


Development of antiviral drugs

Viruses are primitive entities, not quite proper living things, consisting of a genome and sometimes a few enzymes (biocatalysts) stored in a capsule made of protein, and sometimes covered with a lipid (fat) layer. Viruses cannot reproduce on their own, and so they propagate by hijacking cells to do the job for them. Ribbon diagram of the catalytically perfect enzyme TIM. An enzyme is a protein that catalyzes, or speeds up, a chemical reaction. ... Figure 1: Structure of a Lipid. ...


To develop early antivirals, researchers grew cultures of cells and infected them with the target virus. They then introduced chemicals into the cultures thought likely to 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, not very good at discovering antivirals that were effective and had few side effects. It wasn't until the 1980s, when the full genetic sequences of viruses began to be unraveled, that researchers began to learn how viruses worked in detail, and exactly what kinds of molecules were needed to jam their machinery.


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 program.


In either case, the candidates can be synthesized by plugging the gene that synthesizes that protein into bacteria or other kinds of cells. The bacteria or cells are then cultured for mass production of the protein, which can then be sifted by "rapid screening" technologies to see which of the candidates are the most effective.


Antiviral drug design strategies

Researchers working on such "rational design" strategies for developing antivirals have tried to attack viruses at every stage of their life cycles. 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.

The best time to attack a virus is as early as possible in its life cycle. In a sense, this is exactly what vaccines do. Vaccines traditionally consist of a weakened or killed version of a pathogen, though more 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, and so when the real pathogen attacks the subject, the immune system responds to it quickly and blocks it.


Vaccines have an excellent track record for effectiveness, but they are of limited use in treating a patient who has already been infected. That's where antiviral drugs come in.


One approach is to interfere with the ability of a virus to get into a target cell. The virus has to take a sequence of actions 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 payload. 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. Receptor may refer to: In telecommunication, a receiver. ...


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 includes VAP Anti-idiotypic antibodies, anti-receptor antibodies, and natural ligands of the receptor and anti-receptor antibodies. 2. Using agents which mimic the 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 drug can be very expensive. The process of generating anti-idiotypic antibodies is not fully understood. And it has very poor pharmacokinetics.



A number of "entry-inhibiting" or "entry-blocking" drugs are being developed to fight HIV. HIV most heavily targets the immune-system 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 will be more effective. CD4 (cluster of differentiation 4) is a molecule that is expressed on the surface of T helper cells (as well as regulatory T cells and dendritic cells). ... CCR5, short for chemokine (C-C motif) receptor 5, is a chemokine receptor that HIV uses as a co-receptor to enter host cells. ...


However, two entry-blockers, amantadine and rimantadine, have been introduced to combat influenza, and researchers are working on entry-inhibiting drugs to combat hepatitis B and C virus. Amantadine, 1-aminoadamantane, is an antiviral drug that was approved by the FDA in 1976 for the treatment of influenza type A in adults. ... Rimantadine is an orally administered medicine used to treat, and in rare cases prevent, type A influenza. ...


One entry-blocker is pleconaril. 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. ViroPharma Incorporated, a pharmaceutical company, develops and sells drugs that address serious diseases treated by physician specialists and in hospital settings. ... Species Human rhinovirus A (HRV-A) Human rhinovirus B (HRV-B) A rhinovirus is a virus member of the family Picornaviridae. ... The common cold (also known as acute nasopharyngitis) is a mild viral infectious disease of the nose and throat; the upper respiratory system. ... Species Bovine enterovirus Human enterovirus A Human enterovirus B Human enterovirus C Human enterovirus D Human enterovirus E Poliovirus Porcine enterovirus A Porcine enterovirus B The enteroviruses are a genus of (+)ssRNA viruses associated with several human and mammalian diseases. ... Meningitis is inflammation of the membranes (meninges) covering the brain and the spinal cord. ... Encephalitis is an acute inflammation of the brain, commonly caused by a viral infection. ...


A second approach is to target the processes that synthesize virus components after a virus invades a cell. One way of doing this is to develop "nucleotide or nucleoside analogues" that look like the building blocks of RNA or DNA, but jam the enzymes that synthesize the RNA or DNA once the analogue is incorporated.


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. Aciclovir (INN) or aciclovir (USAN), marketed as Zovirax®, is one of the main antiviral drugs. ... Zidovudine (INN) or azidothymidine (AZT) is an antiretroviral drug, the first one approved for treatment of HIV. It is also sold under the names Retrovir® and Retrovis®, and as an ingredient in Combivir® and Trizivir®. It is an analog of thymidine. ...


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 farther and developed inhibitors that do not look like nucleosides, but can still block reverse transcriptase. Lamivudine (2,3-dideoxy-3-thiacytidine, 3TC) is a potent reverse transcriptase inhibitor. ...


Other targets 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; and integrase, which splices the synthesized DNA into the host cell genome. The enzyme RNase H (EC 3. ... Integrase is a protein produced by a virus that enables genetic material that is helpful to the virus, proviral DNA, to be integrated into the DNA of the infected cell. ...


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. The life cycle of an mRNA in a eukaryotic cell. ... In molecular biology, a transcription factor is a protein that binds DNA at a specific promoter or enhancer region or site, where it regulates transcription. ...


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 "mirror images" 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 the works. An antisense structual type that has proven especially valuable in research is Morpholino antisense. Morpholino oligos have been used to experimentally suppress many viral types including caliciviruses [1], flaviviruses (including WNV [2] , Dengue [3] and HCV [4] ), and coronaviruses [5] and are currently in clinical development. Species see text Cytomegalovirus (CMV), is a genus of Herpes viruses; in humans the species is known as Human herpesvirus 5 (HHV-5). ... Morpholino oligos are an antisense technology used to block access of other molecules to specific sequences within nucleic acid molecules. ...


Yet another devious 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 the natural order of things, 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 (from ribonucleic acid enzyme, also called RNA enzyme) is an RNA molecule, that catalyzes a chemical reaction. ...


A ribozyme antiviral to deal with hepatitis C is in field testing, 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.


Some viruses include an enzyme known as a protease that cuts apart viral protein chains 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 odd side-effects, for example causing fat to build up in unusual places. Improved protease inhibitors are now in development. Proteases (proteinases, peptidases or proteolytic enzymes) are enzymes that break peptide bonds between amino acids of proteins. ...


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 and oseltamivir 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. Zanamivir is a neuraminidase inhibitor used in the treatment of and prophylaxis of both influenza A and influenza B. Zanamivir was the first neuraminidase inhibitor commercially developed. ... Oseltamivir (pronounced ah sell TAH mih veer) is an antiviral drug used in the treatment and prophylaxis of both Influenzavirus A and Influenzavirus B. Like zanamivir, oseltamivir is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected... Neuraminidase ribbon diagram Neuraminidase is an antigenic glycoprotein enzyme (EC 3. ...


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 a treatment for hepatitis B and C, and other interferons are also being investigated as treatments for various diseases. Interferons (IFNs) are natural proteins produced by the cells of the immune systems of most animals in response to a challenge by a foreign agents such as viruses, bacteria, parasites and tumour cells. ...


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 another is being tested as a treatment for hepatitis B. Wikipedia does not yet have an article with this exact name. ... The respiratory syncytial virus (RSV or RS virus) causes a common viral infection of infants and young children. ...


Examination of the genomes of viruses and comparison with the human genome show that some are devious, generating proteins that mimic those used by the human immune system, confusing the immune-system response. Researchers are now hunting for antivirals that can recognize these intruder proteins and disable them.


All drugs designed to fight pathogens have a common problem: over the long run, the pathogens evolve to acquire resistance to the drugs. This means that no antiviral will ever be a permanent solution. In fact, the structure of an antiviral compound will have to be tweaked as its target pathogen changes.


This is the nature of the game. However, antivirals are now promising to be the biggest innovation in pharmaceuticals since the introduction of antibiotics during the Second World War, and promise to be a major step forward in health care.


See also


Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. Different classes of antiretroviral drugs act at different stages of the HIV life cycle. ... This is a list of antiviral drugs. ...

Antivirals (ATC J05A) edit
Anti-herpesvirus agents   Acyclovir · Cidofovir · Docosanol · Famciclovir · Foscarnet · Fomivirsen · Ganciclovir · Idoxuridine · Penciclovir · Trifluridine · Tromantadine · Valaciclovir · Valganciclovir · Vidarabine
Anti-influenza agents Amantadine · Oseltamivir · Peramivir · Rimantadine · Zanamivir
 
Antiretroviral drugs   NRTIs Zidovudine · Didanosine · Stavudine · Zalcitabine · Lamivudine · Abacavir · Tenofovir
NNRTIs   Nevirapine · Efavirenz · Delavirdine
PIs Saquinavir · Indinavir · Atazanavir · Ritonavir · Nelfinavir · Amprenavir · Lopinavir · Tipranavir
 
Other antiviral agents Fomivirsen · Enfuvirtide · Imiquimod · Interferon · Ribavirin · Viramidine

  Results from FactBites:
 
Antiviral drug - Wikipedia, the free encyclopedia (2199 words)
Antiviral drugs are one class of antimicrobials, a larger group which also includes antibiotics, anti-fungal and anti-parasitic drugs.
However, two entry-blockers, amantadine and rimantadine, have been introduced to combat influenza, and researchers are working on entry-inhibiting drugs to combat hepatitis B and C virus.
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 the works.
  More results at FactBites »

 
 

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