How Do Antiviral Drugs Work?
What are antiviral drugs?1,2
Antiviral drugs are medications that are used to treat viral infections by either curing or controlling the infection. Viruses cause illnesses such as HIV/AIDS, Covid-19, influenza, herpes simplex type I (cold sores of the mouth) and type II (genital herpes), herpes zoster (shingles), viral hepatitis, encephalitis, infectious mononucleosis, and the common cold. Viruses are infectious particles or agents of small size that can multiply or replicate only in living cells of humans, animals, plants, or bacteria. The name virus has its root in the Latin word that means “slimy liquid” or “poison.”
Most antiviral agents target specific viruses, while a broad-spectrum antiviral, which is more ideal, is effective against a wide range of viruses, similar to a broad-spectrum antibiotic that can treat multiple types of bacterial infection. Unlike most antibiotics, however, antiviral drugs do not destroy their target pathogen--the organism causing the disease; instead, they block its replication or propagation through progeny generation, and thereby control the viral infection from causing any further harm to our body. Both antivirals and antibiotics fall in the class of antimicrobial drugs, along with antifungal and antiparasitic drugs.
A brief history of antiviral drugs1
The first experimental antivirals were developed in the 1960s, primarily targeting herpes viruses, using traditional trial-and-error drug discovery methods. Researchers grew cultures of cells in the laboratory and infected them with the target virus to mimic a model of infection that happens in our body. They then treat this tissue culture model with chemicals which they thought might inhibit viral replication and observed whether the quantity of virus particles in the cultures increased or decreased, in other words, blind screening with no efforts towards drug development for specific virus or virus-specific mechanism of replication. In the blind-screening method, chemicals that seemed to have an effect, with tolerable side-effects, were selected for further investigation. As you can imagine, this hit-or-miss approach is rather time-consuming. Without knowing how the target virus worked, the discovery of effective antivirals proved to be inefficient. This approach changed in the 1980s when full genetic information of viruses was becoming available. This revolutionary introduction of viral genetic codes allowed researchers to methodically scrutinize how different types of viruses multiply and select chemicals in an intelligent manner that can purposely throw a wrench into their reproductive cycle.
Antiviral drug families1,2,3
Most of the antiviral drugs available today are targeted for HIV, herpes, hepatitis B and C, influenza A and B, and Covid-19 viruses. Scientists and clinicians are working to grow the list of antivirals to include targets against other families of viruses. Antiviral medications come in the form of capsules, tablets, liquids, ointments, and injectables. The recommended dosage may vary based on the type of antiviral drug and the infection that is being treated. Dosage may also vary for different people. We currently have several different medications in the antiviral drug family. Main ones include:
Acyclovir (brand name, Zovirax)--used to treat chickenpox, shingles, and the symptoms of herpes virus infections of the genitals, lips, mouth, skin, and brain. Acyclovir does not cure the infections; it relieves the discomfort and shortens the time to heal sores.
Valacyclovir (brand name, Valtrex) and famciclovir (brand name, Famvir)—are also used to relieve the symptoms of shingles.
Ganciclovir (brand name, Cytovene)--is used to treat cytomegalovirus (CMV) eye infections in people with compromised or weak immune systems. This antiviral does not cure the CMV infection, but it may keep the symptoms from getting worse. Ganciclovir may also be used as a prophylactic to help prevent CMV infections in people who are about to undergo treatments such as organ or bone marrow transplant that will weaken their immune systems.
Amantadine (brand name, Symmetrel) and rimantadine (brand name, Flumadine)--are prescribed to prevent or treat certain kinds of influenza (flu) virus. These are essentially flu medicines. They are typically administered either alone or in combination with flu shots.
Antiretroviral drugs--another class of antiviral drugs that target a specific type of virus called a retrovirus. An example of a retrovirus is the human immunodeficiency virus (HIV), the virus that causes AIDS.
Antiviral Drug Design & Development1
Despite about 70 years of antiviral research, our collection of antiviral drugs remains surprisingly small. Currently, there are more than 80 antiviral drugs (see the list in the table below), most of which are directed against HIV and herpesviruses.
| Trade Name | Generic Name (Abbreviation) | Target Virus Treatment |
|---|---|---|
| Retrovir | Zidovudine (AZT) | HIV-1 |
| Intron A | Interferon Alfa-2B (INT2B) | HPV |
| Cytovene | Ganciclovir Sodium (GAN) | CMV |
| Alferon N Injection | Interferon Alfa-N3 (INTN3) | HPV |
| Intron A | Interferon Alfa-2B (INT2B) | HCV |
| Foscavir | Foscarnet Sodium (FOS) | CMV |
| Videxa | Didanosine (ddI) | HIV-1 |
| Hivida | Zalcitabine (ddC) | HIV-1 |
| Intron A | Interferon Alfa-2B (INT2B) | HBV |
| Flumadine | Rimantadine (RIM) | Influenza |
| Zerit | Stavudine (d4T) | HIV-1 |
| Famvira | Famciclovir (FAM) | HSV |
| Valtrex | Valacyclovir Hydrochloride (VAL) | HSV |
| Epivir | Lamivudine (3TC) | HIV-1 |
| Invirase | Saquinavir Mesylate (SQV) | HIV-1 |
| Norvir | Ritonavir (RTV) | HIV-1 |
| Crixivan | Indinavir Sulfate (IDV) | HIV-1 |
| Viramune | Nevirapine (NVP) | HIV-1 |
| Vistidea | Cidofovir (CID) | CMV |
| Denavir | Penciclovir (PEN) | HSV |
| Aldara | Imiquimod (IMI) | HPV |
| Viracepta | Nelfinavir Mesylate (NFV) | HIV-1 |
| Rescriptor | Delavirdine Mesylate (DLV) | HIV-1 |
| Combivir | Lamivudine (3TC)/Zidovudine (AZT) | HIV-1 |
| Infergen | Interferon Alfacon-1 (INTA1) | HCV |
| Synagis | Palivizumab (PAV) | RSV |
| Rebetol | Ribavirin (RIB) | HCV |
| Vitravenea | Fomivirsen Sodium (FOM) | CMV |
| Sustiva | Efavirenz (EFV) | HIV-1 |
| Epivir-HBV | Lamivudine (3TC) | HBV |
| Ziagen | Abacavir Sulfate (ABC) | HIV-1 |
| Agenerasea | Amprenavir (APV) | HIV-1 |
| Relenza | Zanamivir (ZAN) | Influenza |
| Tamiflu | Oseltamivir (OSE) | Influenza |
| Abreva | Docosanol (DOC) | HSV |
| Kaletra | Lopinavir (LPV)/Ritonavir (RTV) | HIV-1 |
| Trizivir | Abacavir Sulfate (ABC)/Lamivudine (3TC)/Zidovudine (AZT) | HIV-1 |
| Pegintron/Sylatron | Peginterferon Alfa-2B (PEG2B) | HCV |
| Valcyte | Valganciclovir Hydrochloride (VALG) | CMV |
| Viread | Tenofovir Disoproxil Fumarate (TDF) | HIV-1 |
| Hepsera | Adefovir Dipivoxil (ADE) | HBV |
| Pegasys | Peginterferon Alfa-2A (PEG2A) | HCV |
| Fuzeon | Enfuvirtide (T20) | HIV-1 |
| Reyataz | Atazanavir Sulfate (ATV) | HIV-1 |
| Emtriva | Emtricitabine (FTC) | HIV-1 |
| Lexiva | Fosamprenavir Calcium (FPV) | HIV-1 |
| Epzicom | Abacavir Sulfate (ABC)/Lamivudine (3TC) | HIV-1 |
| Truvada | Emtricitabine (FTC)/Tenofovir Disoproxil Fumarate (TDF) | HIV-1 |
| Baraclude | Entecavir (ENT) | HBV |
| Pegasys | Peginterferon Alfa-2A (PEG2A) | HBV |
| Aptivus | Tipranavir (TPV) | HIV-1 |
| Prezista | Darunavir Ethanolate (DRV) | HIV-1 |
| Atripla | Efavirenz (EFV)/Emtricitabine (FTC)/Tenofovir Disoproxil Fumarate (TDF) | HIV-1 |
| Tyzekaa | Telbivudine (TEL) | HBV |
| Veregen | Sinecatechins (SIN) | HPV |
| Selzentry | Maraviroc (MVC) | HIV-1 |
| Isentress | Raltegravir Potassium (RAL) | HIV-1 |
| Intelence | Etravirine (ETR) | HIV-1 |
| Viread | Tenofovir Disoproxil Fumarate (TDF) | HBV |
| Xerese | Acyclovir/Hydrocortisone (ACY) | HSV |
| Victrelis | Boceprevir (BOC) | HCV |
| Victrelis | Boceprevir (BOC) | HCV |
| Edurant | Rilpivirine Hydrochloride (RPV) | HIV-1 |
| Inciveka | Telaprevir (TELA) | HCV |
| Complera | Emtricitabine (FTC)/Rilpivirine Hydrochloride (RPV)/Tenofovir Disoproxil Fumarate (TDF) | HIV-1 |
| Stribild | Cobicstat (COBI)/Elvitegravir (EVG)/Emtricitabine (FTC)/Tenofovir Disoproxil Fumarate (TDF) | HIV-1 |
| Tivicay | Dolutegravir Sodium (DTG) | HIV-1 |
| Olysio | Simeprevir Sodium (SIM) | HCV |
| Sovaldi | Sofosbuvir (SOF) | HCV |
| Triumeq | Abacavir Sulfate (ABC)/Dolutegravir Sodium (DTG)/Lamivudine (3TC) | HIV-1 |
| Vitekta | Elvitegravir (EVG) | HIV-1 |
| Harvoni | Ledipasvir (LED)/Sofosbuvir (SOF) | HCV |
| Rapivab | Peramivir (PER) | Influenza |
| Viekira Pak | Dasabuvir Sodium (DAS)/Ombitasvir (OMB)/Paritaprevir (PAR)/Ritonavir (RTV) | HCV |
| Prezcobix | Cobicstat (COBI)/Darunavir Ethanolate (DRV) | HIV-1 |
| Evotaz | Atazanavir Sulfate (ATV)/Cobicstat (COBI) | HIV-1 |
| Dutrebisa | Lamivudine (3TC)/Raltegravir (RAL) | HIV-1 |
| Daklinza | Daclatasvir Dihydrochloride (DAC) | HCV |
| Technivie | Ombitasvir (OMB)/Paritaprevir (PAR)/Ritonavir (RTV) | HCV |
| Genvoya | Cobicstat (COBI)/Elvitegravir (EVG)/Emtricitabine (FTC)/Tenofovir Alafenamide Fumarate (TAF) | HIV-1 |
| Zepatier | Elbasvir (ELB)/Grazoprevir (GRA) | HCV |
| Odefsey | Emtricitabine (FTC)/Rilpivirine Hydrochloride (RPV)/Tenofovir Alafenamide Fumarate (TAF) | HIV-1 |
| Descovy | Emtricitabine (FTC)/Tenofovir Alafenamide Fumarate (TAF) | HIV-1 |
| Epclusa | Sofosbuvir (SOF)/Velpatasvir (VEL) | HCV |
| Vemlidy | Tenofovir Alafenamide Fumarate (TAF) | HBV |
| Vosevi | Sofosbuvir (SOF)/Velpatasvir (VEL)/Voxilaprevir (VOX) | HCV |
| Mavyret | Glecaprevir (GLE)/Pibrentasvir (PIB) | HCV |
| Prevymis | Letermovir (LET) | CMV |
| Juluca | Dolutegravir (DTG)/Rilpivirine (RPV) | HIV-1 |
| Veklury | Remdesivir | COVID-19 |
Abbreviations for Viruses
HIV-1= Human immunodeficiency virus-1
HCV= Hepatitis C virus
HBV= Hepatitis B virus
CMV= Cytamegalovirus
HSV= Herpes simplex virus
HPV= Human papillomavirus
COVID-19= Coronavirus disease 2019
Developing antiviral medicines has been difficult because most drugs that kill viruses also damage the human cells that are infected. Viruses are tiny particles that are too small to be seen with naked eyes. When looked under an electron microscope, a virus particle is a core of genetic material (DNA or RNA), surrounded by a protective protein coat or a capsule. Viruses are not considered living things since they cannot reproduce on their own. They need to invade the cells of other living things, such as humans and animals, and hijack the host cells' machinery to make more copies of themselves. Depending on the type of virus, one infectious virus particle can produce millions of progeny particles in a single infected cell. Once inside the host cells, viruses multiply vigorously, spread through the body, and ultimately cause illness. Some illnesses such as common colds, flu, measles, mumps, and chickenpox, can come and go—these are acute infections. Others, such as HIV, cytomegalovirus, and Epstein-Barr virus, can linger for life—these are persistent infections.
With the advent of molecular virology and DNA cloning technology, viral genes that are important for replication can be created in the lab and expressed in organisms, such as bacteria or other cells. The products or proteins made from expressing the cloned viral genes can be purified and analyzed in molecular detail. These scientific advancements trailblazed a path for virologists to scrutinize the life cycles of many viruses, revealing many targets for treatment intervention. Antiviral drugs block steps in the viral replication process through which they reproduce. The idea is to identify viral proteins or parts of proteins and or building blocks of their genetic materials that can be disabled. Little focus is placed on killing the viruses. To reduce the likelihood of side effects, these drug targets are generally selected against proteins or parts of proteins that are uncommon in humans. Although for broad effectiveness, the targets are selected for proteins that are similar across many strains of a virus or even common among different species of viruses in the same family. For instance, a critical enzyme that is made only by the virus and is common across different strains, but is not made by the infected person, is a good antiviral target for interference.
Viral life cycles consist of the following steps in general 1
- Attachment to a host (eg, human) cell
- Release of viral genes and sometimes enzymes and proteins into the host cell
- Replication or copying of viral structural components using host-cell machinery
- Assembly of viral components into progeny virus particles
- Release of viral particles from the infected (eg, human) cells
- Infect new hosts or uninfected cells in the same (eg, human) host
Important viral replication or virus life cycle stage targets in the antiviral drug discovery can include 1
- Attachment proteins on the surface of the virus that interact with our cells before cell entry or penetration. Enfuvirtide (brand name Fuzeon) is an antiviral against the HIV virus that works by inhibiting viral entry into the hast cell.
- Penetration of the virus particle into our cells and uncoating of the virus’ outermost layer to dump and release its genetic materials into our cells. Amantadine and rimantadine treat influenza viruses by blocking penetration and uncoating.
- Viral mRNA production by which the mRNA is copied off of viral DNA segments that code for essential proteins
- Protein synthesis necessary for viral replication and building blocks for progeny virus
- DNA synthesis or copying of the genetic materials to be incorporated into each new progeny virus. Acyclovir is a nucleoside analog that is used to treat herpes virus infections. Nucleosides are building blocks of DNA. Nucleotide analogous mimic the natural nucleotides, but they block DNA replication.
- Production of nucleoside or building blocks of genetic materials (ie, DNA, RNA)
- Eliminating functional nucleosides.
- Processing of glycoproteins that are located on the protective outer shell or the envelope of the virus particles
- Virus particle integrity (eg, the outer layer or envelope encasing the viral genetic material) during the virus assembly phase. Rifampicin is an antiviral drug that inhibits the assembly phase. Some viruses, such as HIV viruses, bring in their own enzyme known as a protease that cuts viral protein chains so they can be assembled into their final configuration. Protease inhibitors are also antiviral targets.
- Proteins and components involved in the release phase. Zanamivir (Relenza) and oseltamivir (Tamiflu), treatments for influenza, prevent the release of viral particles by blocking a molecule named neuraminidase that is found on the surface of flu viruses. Neuraminidase is the same across a wide range of flu strains.
Antivirals for COVID-194,5
The outbreak of SARS-CoV-2 in Wuhan, China in December 2019 has strapped us into a much-dreaded global pandemic. Although many antiviral candidates are currently being investigated, only one is approved for the treatment of Covid-19. The U.S. Food and Drug Administration approved the antiviral drug Veklury (remdesivir) on October 22, 2020, for adults and children 12 years of age and older and weighing at least 40 kilograms (~88 pounds) for the treatment of Covid-19 requiring hospitalization. Veklury (remdesivir) is the first FDA-approved treatment for Covid-19. It is a nucleotide analog, RNA polymerase inhibitor. A total of 1062 patients were evaluated in a clinical study with 541 receiving remdesivir and 521 receiving an inactive control product or placebo (in order to compare and measure the actual effectiveness of the drug itself). Remdesivir showed improvement in recovery time by 5 days, although there was no improvement in survival rate. Those who received remdesivir had a median recovery time of 10 days compared to 15 days among those who received the inactive placebo.
Several months into the pandemic, scientists have discovered the genomic structure, characteristics, and disease-causing mechanisms of SARS-CoV-2. This information has been instrumental in identifying potential drug candidates for evaluating treatments for Covid-19. To date, a total of 98 studies are looking at potential antivirals for Covid-19. Other than remdesivir, these drugs include broad-spectrum antivirals such as umifenovir, protease inhibitors such as lopinavir/ritonavir, and favipiravir. Other antiviral drugs that are being investigated for Covid-19 include the nucleosidase inhibitors and polymerase acidic endonuclease inhibitors, which are currently approved for influenza infections. Although some of these drugs may be promising, more clinical trials currently in progress are necessary for reliable and quality data.
Host Immune System Stimulation
Another approach to fighting viruses involves stimulating the host immune system to attack the pathogens, instead of attacking it directly. The advantage of this approach is that it can be used to attack a range of viruses. One of the well-known classes of antiviral drugs in this category is interferons. Interferons are used as a standard treatment for hepatitis B and C.
A more specific approach is the use of antibodies. Antibodies are proteins that can bind to a virus and mark it for attack by other components of the immune system. Once a suitable target on the virus is identified, loads of identical or monoclonal antibody copies can be made to bind to that target. A monoclonal drug is used to treat the respiratory syncytial virus in children.
Antiviral drug resistance1
Antiviral resistance occurs when viruses become susceptible, either by decreased or no effectiveness, to a drug due to changes in its genome. Antiviral drug resistance remains a major challenge to antiviral therapy. Antiviral resistance occurs because the viral genome (DNA or RNA) is constantly changing or mutating when replicating throughout the course of antiviral treatment. Each replication provides the opportunity for mutations that encode for antiviral resistance to occur.
RNA viruses such as hepatitis C and influenza A have high error rates during genome replication because of RNA polymerases (enzymes necessary for replicating RNA) lack proofreading function. Therefore, RNA viruses are more likely to become resistant than DNA viruses. DNA viruses, such as HPV and herpesvirus, hijack our cellular replication machinery, which gives them proofreading capabilities during genome copying. DNA viruses are therefore less error-prone and are more slowly evolving than RNA viruses. Immunocompromised individuals hospitalized with pneumonia are at the highest risk of developing oseltamivir (Tamiflu) resistance to the flu viruses.
Antivirals have the potential to promote or prevent the rise of resistant viruses. Mutations happen only during viral genome replication. Consequently, if replication is blocked, no antiviral resistant viruses can emerge. If an individual carrying a small load of viral genome with no relevant pre-existing mutation is given a sufficient dose of the antiviral to block all viral replication, the infection should be in check. On the other hand, if the same drug is given after the viral population has increasingly multiplied, or if the drug is administered at an insufficient level to block replication completely, the mutant viruses will thrive and continue to multiply and evolve.
Sometimes resistance to an antiviral drug will require multiple mutations rather than a single mutation. In the case where multiple mutations are required, the chances of generating a virus containing all the required mutations are much lower than a virus containing a single required mutation. In any case, if replication continues in the presence of the antiviral agent, resistant mutant viruses will accumulate in number.
Sometimes combination therapy of 2 or more antiviral drugs are used to combat the resistance issue. Simultaneous use of 2 or more antiviral drugs often leads to more effective killing of the viruses. However, the combination therapy does not always lead to sufficient clearance of infection. If for instance therapy is given late in the disease progression, or if the combined potency of the drugs is less than optimal, drug resistance will still occur.
Antiviral doses should not be missed. To make sure that the infection clears up completely, this medicine should be taken for as long as instructed by the doctor. People should not stop taking the drug just because symptoms begin to improve.
Main Sources (other than the embedded links):
Flint SJ, Enquist LW, Racaniello VR, Skalka AM. Principles of Virology: Molecular Biology, Pathogenesis, and Control of Animal Viruses. 2nd ed. Washington, DC: ASM Press; 2004
Antiviral Drug FAQ.org. http://www.faqs.org/health/topics/78/Antiviral-drugs.html, Accessed Oct 11, 2020
Antiviral Drug. https://www.britannica.com/science/antiviral-drug. Accessed October 11, 2020.
John H. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 — Final Report. NEJM. 2000; DOI: 10.1056/NEJMoa2007764
Teoh SL, Lim YH, Lai NM, et al. Directly Acting Antivirals for COVID-19: Where Do We Stand? Frontiers in Microbiology. 2000; 11. DOI: 10.3389/fmicb.2020.01857
