Some science behind the scenes

Antiviral drugs

Antiviral drugs are a class of synthetically produced drugs designed to target viruses. As the human body is well able to deal with the majority of viruses itself, these drugs target some very specific virulent and life threatening illnesses that the body either cannot fight by itself, or struggles to win against. The main four are: 

  • HIV

  • Herpes

  • Hepatitis

  • Influenza

Synthetic anti-virals are a relatively new type of drug. Only in the 1980s, when the full genetic sequences of viruses began to be unraveled, did researchers begin to learn how viruses worked in detail, and exactly what chemicals were needed to thwart their reproductive cycle.

Pharmaceutical drugs these days tend to be ‘designed’. 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. They aim to make these "targets" as unlike any proteins or parts of proteins in humans as possible, to reduce the likelihood of side effects. The targets are made to 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 – a time and money saving tactic. For example, a researcher might target a critical enzyme synthesized by the virus that is common across strains, and see what can be done to interfere with its operation.

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

Before cell entry

One anti-viral strategy is to interfere with the ability of a virus to infiltrate a target cell. 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.

  • Using agents which mimic the cellular receptor and bind to the VAP.

This strategy of designing drugs can be very expensive, and since the process is partly trial and error, it can be a relatively slow process.

Entry inhibition

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, for example, HIV.

Uncoating inhibitor

Inhibitors of uncoating have also been investigated. Amantadine and rimantadine, have been introduced to combat influenza.

During viral synthesis

This approach targets the processes that synthesise 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 deactivate the enzymes that synthesize the RNA or DNA once the analogue is incorporated.

Other targets include integrase which splices the synthesized DNA into the host cell genome and RNase H - which is a component of reverse transcriptase that splits the synthesized DNA from the original viral RNA . Several antivirals are now being designed to block attachment of transcription factors to viral DNA.

An entirely new type of drug is 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.

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.

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.

Assembly

There are very few drugs that target this area.

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.

 On poisoning

 Chronic poisoning is long-term repeated or continuous exposure to a ‘poison’ where symptoms do not occur immediately or after each exposure. The patient gradually becomes ill, or becomes ill after a long latent period. Chronic poisoning most commonly occurs following exposure to poisons that bio-accumulate.

Many substances regarded as poisons are toxic only indirectly, by toxication. Many drug molecules are made toxic in the liver, and the genetic variability of certain liver enzymes makes the toxicity of many compounds differ between individuals.

So in the first place the amount of a substance may determine whether it is poisonous or not and the genetic make-up of a person may also determine whether something is poisonous or not.

All antivirals work at the genetic level, which means that there is the real possibility that they will be toxic – a poison to one set of people and not toxic to others. It has for example already been seen that antivirals act differently on Japanese people to ‘Caucasians’, but even within broad racial groups differences can be observed. Here it is the kidney which is being affected, but the principle is the same…

 

Genetic variants of ABCC10, a novel tenofovir transporter, are associated with kidney tubular dysfunction - Pushpakom SP, Liptrott NJ, Rodríguez-Nóvoa S, Labarga P, Soriano V, Albalater M, Hopper-Borge E, Bonora S, Di Perri G, Back DJ, Khoo S, Pirmohamed M, Owen A.; National Institute for Health Research Biomedical Research Centre, Royal Liverpool Hospital, UK.

BACKGROUND:  Tenofovir (TFV) causes kidney tubular dysfunction (KTD) in some patients, but the mechanism is poorly understood. Genetic variants in TFV transporters are implicated; we explored whether ABCC10 transports TFV and whether ABCC10 single-nucleotide polymorphisms (SNPs) are associated with KTD……………….
CONCLUSIONS:  TFV is a substrate for ABCC10, and genetic variability within the ABCC10 gene may influence TFV renal tubular transport and contribute to the development of KTD. These results need to be replicated in other cohorts

 We have already seen that the general idea behind modern antiviral drug design is to identify viral proteins, or parts of proteins, that can be disabled. Researchers aim to make these "targets" as unlike any proteins or parts of proteins in humans as possible, to reduce the likelihood of side effects. But we have also seen that viruses base themselves on our genes - the nucleic acids of many viruses contain DNA sequences similar to those of their host cells. So here we have the possibility for it all to go terribly wrong. Get the drug just a little bit wrong and it targets our DNA [or RNA] and not that of the virus – or it may target both.

 

Side effects of long-term oral antiviral therapy for hepatitis B - Fontana RJ; Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109-0362, USA.

The aim of this review is to summarize the safety profile of the five approved oral nucleoside analogs used to treat chronic hepatitis B virus (HBV) infection, focusing on both the class adverse effects and those that have been reported with individual agents, as well as their safety in pregnancy.
All nucleoside analogs have a "Black Box" warning because of their potential for inhibition of human DNA polymerase gamma involved in mitochondrial DNA replication. A reduction in intracellular mitochondrial DNA levels can lead to varying clinical manifestations of mitochondrial toxicity (i.e., neuropathy, myopathy, lactic acidosis), but these side effects are rarely reported with the oral antiviral agents active against HBV. ………..

 Alternatively it targets neither and simply acts as a poison

Drugs for which no data is available

Ampligen - also known as poly I:poly C12U, was an experimental immunomodulatory double stranded RNA drug proposed as a treatment for chronic fatigue syndrome (CFS) and acquired immunodeficiency syndrome (AIDS). The company developing the drug filed a new drug application (NDA) with the FDA to market and sell Ampligen for the treatment of CFS, but this was rejected in December 2009

Arbidol - is an antiviral treatment for influenza infection used in Russia and China. It is not approved for use in Western countries. The drug inhibits viral entry into target cells, and also stimulates the immune response

Boceprevir - trade name Victrelis, is a protease inhibitor used as a treatment for hepatitis C. It binds to HCV nonstructural 3 (NS3) active site. It was approved by the FDA in May 2011.

Cidofovir - is an injectable antiviral medication for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS. It suppresses CMV replication by selective inhibition of viral DNA polymerase and therefore prevention of viral replication and transcription. It is an acyclic nucleoside phosphonate

Darunavir - brand name Prezista, formerly known as TMC114 is a drug used to treat HIV infection. It is in the protease inhibitor class.

Delavirdine - brand name Rescriptor is a non-nucleoside reverse transcriptase inhibitor (NNRTI). It is used for the treatment of human immunodeficiency virus (HIV) type 1. Although delavirdine was approved by the U.S. Food and Drug Administration in 1997, its efficacy is lower than other NNRTIs, and it also has an inconvenient schedule. These factors have led the U.S. DHHS not to recommend its use as part of initial therapy. It is currently rarely used.

Docosanol - also known as behenyl alcohol, is a saturated fatty alcohol used traditionally as an emollient, emulsifier, and thickener in cosmetics, nutritional supplement and more recently, in an FDA approved pharmaceutical, Abreva, approved as an antiviral agent for reducing the duration of cold sores caused by the herpes simplex virus.

Edoxudine - or edoxudin is used for herpes simplex virus

Entecavir - Is an oral antiviral drug used in the treatment of hepatitis B infection. It is marketed under the trade name Baraclude & Entavir. Entecavir is a nucleoside analog that inhibits reverse transcription, DNA replication and transcription in the viral replication process.

Etravirine - brand name Intelence, is used for the treatment of HIV. It is a non-nucleoside reverse transcriptase inhibitor (NNRTI).

Famciclovir - is an antiviral drug used for the treatment of various herpesvirus infections, most commonly for herpes zoster (shingles). It is a prodrug form of penciclovir with improved oral bioavailability. Famciclovir is marketed under the trade name Famvir.

Fomivirsen - brand name Vitravene is used in the treatment of cytomegalovirus retinitis (CMV) in immunocompromised patients, including those with AIDS. It was licenced in 1998. It is an oligonucleotide that blocks translation of viral mRNA by binding to a coding segment of a key CMV gene. It was the first antisense antiviral approved by the FDA

Fosamprenavir - marketed under the trade names Lexiva and Telzir is a pro-drug of the protease inhibitor and antiretroviral drug amprenavir. The human body metabolizes fosamprenavir in order to form amprenavir, which is the active ingredient. That metabolization increases the duration that amprenavir is available, making fosamprenavir a slow-release version of amprenavir

Foscarnet - marketed under the trade name Foscavir is used to treat herpes viruses, including drug resistant cytomegalovirus (CMV) and herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2). It is also used to treat CMV retinitis.

Imunovir - Inosine pranobex (Isoprinosine or Methisoprinol) is a combinatinon of inosine, acetamidobenzoic acid, and dimethylaminoisopropanol used as an antiviral drug. Inosine pranobex has no effect on viral cells itself. It acts as a powerful immunostimulant. It is used to treat the rare measles complication subacute sclerosing panencephalitis in conjunction with intrathecal interferon therapy

Idoxuridine - is an anti-herpesvirus antiviral drug. It is a nucleoside analogue, a modified form of deoxyuridine, similar enough to be incorporated into viral DNA replication, but the iodine atom added to the uracil component blocks base pairing. It is used only topically due to cardiotoxicity

Loviride - was an antiviral drug active against HIV, that entered phase III clinical trials in the late 1990s but failed to gain approval

Maraviroc -brand-named Selzentry, or Celsentri is an antiretroviral drug used in the treatment of HIV infection. It is an entry inhibitor.

Methisazone - is an antiviral drug that works by inhibiting mRNA and protein synthesis, especially in pox viruses. It has been used in the past to treat smallpox. Methisazone has been in use since at least 1965

Penciclovir - is used for the treatment of various herpesvirus infections. It is a nucleoside analogue. Because penciclovir is absorbed poorly when given orally it is used more as a topical treatment, and is the active ingredient in the cold sore medications Denavir, Vectavir and Fenistil. Famciclovir is a prodrug of penciclovir with improved oral bioavailability

Raltegravir - brand name Isentress is an antiretroviral drug, used to treat HIV infection, the first of a new class of HIV drugs, the integrase inhibitors, to receive such approval

Rilpivirine - brand name Edurant is used for the treatment of HIV infection. It is a non-nucleoside reverse transcriptase inhibitor (NNRTI) Rilpivirine entered phase III clinical trials in 2008, and was approved for use in the United States in 2011. A fixed-dose drug combining rilpivirine with emtricitabine and tenofovir, was approved in 2011 under the brand name Complera

Saquinavir - is an antiretroviral drug used in HIV therapy. It falls in the protease inhibitor class. Two formulations have been marketed:

  • a hard-gel capsule formulation of the mesylate, with trade name Invirase, which requires combination with ritonavir to increase the saquinavir bioavailability;

  • a soft-gel capsule formulation of saquinavir, with trade name Fortovase

Trifluridine - also called trifluorothymidine or TFT is an anti-herpesvirus antiviral drug, used primarily on the eye. It was sold under the trade name, Viroptic. It is a nucleoside analogue,

Tromantadine - is used to treat herpes simplex virus. It is available in a topical gel under trade name Viru-Merz.  Like rimantadine and amantadine, tromantadine is a derivative of adamantane. Tromantadine inhibits the early and late events in the virus replication cycle. It changes the glycoproteins of the host cells, therefore impeding the absorption of the virus. It inhibits penetration of the virus. It also prevents uncoating of the virions

Valganciclovir hydrochloride - Valcyte, Cymeval, Valcyt, Valixa, Darilin, Rovalcyte, Valcyte, Patheon, Syntex is an antiviral medication used to treat cytomegalovirus infections. It is a prodrug for ganciclovir.

Vidarabine - or adenine arabinoside is an antiviral drug which is active against herpes simplex and varicella zoster viruses.

Zalcitabine - also called ddC and dideoxycytidine, has the trade name Hivid. This drug has been discontinued by the manufacturer. 

Observations

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