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Infectious Diseases

Infectious Disease information and resources for the MSK community, including clinicians, patients, and the general public.

Antiviral Targets

Antivirals are any drug that is used to treat a viral infectious disease. Most antivirals only target specific viruses. Antivirals are classified based on their targets, which can be either host or viral factors.

Virus-directed antivirals bind to the viral proteins or nucleic acids involved in viral entry, transcription, replication of the viral genome, assembly, and release of infectious viral particles.

Host-directed antivirals control the activity of factors and pathways within the host that are involved the creation and transport of the building blocks vital to the virus, as well the immune system's response.

To date, about a hundred mono- and combination antiviral therapies have been approved, the majority of which target Human Immunodeficiency Virus (HIV), a retrovirus.

Antiviral agents target specific stages or steps in the viral life cycle:
  1. Viral entry - Reverse Transcriptase Inhibitors
  2. Viral synthesis - Integrase Inhibitors
  3. Transcription - Transcription Factor Antivirals
  4. Translation - Antisense and Ribozyome Antivirals
  5. Protein processing - Protease Inhibitors
  6. Release - Neuraminidase Inhibitors

RT Inhibitors

Reverse Transcriptase Inhibitors (RTIs) work by developing nucleotide or nucleoside analogues that look like the the ones that form DNA and RNA, but instead trick the virus by deactivating the enzymes (reverse transcriptase) that synthesize the DNA or RNA.

There are two main types of RT inhibitors: nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs).

Acyclovir (ACV) was the first successful antiviral. It is is effective against herpesvirus infections. It is used to treat herpes simplex virus infections, chickenpox, and shingles. It's also been used to prevent cytomeglovirus (CMV) infections in transplant patients as well as complications from Epstein-Barr Virus (EBV) infections.

Azidothymidine (AZT) was the first antiviral drug approved for treating HIV. AZT was originally dosed as twice daily. This two-dose regime has been referred to as Highly Active Antiretroviral Therapy (HAART) and is used to prevent the likelihood of HIV resistance.  Beginning in 2019, the standard treatment became a once-daily three drug combination that includes AZT.

Integrase Inhibitors

Retroviral Integrase (IN) is an enzyme produced by retroviruses that is integrated into the host cell genome. Integrase Inhibitors block Retroviral Integrase.

Raltegravir (brand name Isentress) was the first integrase inhibitor to receive FDA approval in 2007 to treat HAART-resistant HIV and in 2009 was expanded for use in all HIV patients. The drug is also active against Human Endogenous Retroviruses (HERVs) and possibly Epstein–Barr virus, which have been suggested in the pathogenesis of relapsing-remitting MS.

Elvitegravir (EVG) received FDA approval in 2012 for use in adult patients starting HIV treatment for the first time as part of the fixed dose combination known as Stribild. In 2014 the FDA approved Elvitegravir as a single pill formulation under the trade name Vitekta. In 2015 the FDA approved the drug for use in patients affected with HIV-1 as a part of a second fixed dose combination pill known as Genvoya.

In the United States, elvitegravir can be obtained either as part of the combination pills Stribild or Genvoya, or as the single pill formulation Vitekta.

Vitekta is FDA approved to be used for the treatment of HIV-1 infection in adults who have previous treatment experience with antiretroviral therapy. It must be used in combination with a protease inhibitor that is coadministered with ritonavir as well as additional antiretroviral drug(s).

Transcription Inhibitors

There are currently sveral antivirals are now being designed to block attachment of transcription factors to viral DNA.

Antisense Antivirals

Antisense 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, thus inhibiting translation.

Fomivirsen (brand name Vitravene) was the first an antisense antiviral approved by the FDA to treat CMV in immunocompromised AIDS patients. It works by blocking translation of viral mRNA by binding to the complementary sequence of the mRNA transcribed from the template segment of a key CMV gene UL123, which encodes the CMV protein IE2.

Ribozyome Antivirals

Ribozyomes (ribonucleic acid enzymes) are RNA enzymes that catalyze biochemical reactions necessary for RNA splicing. Synthetic ribozyomes are used to cut apart viral DNA and RNA at specific sites in order to disable them.

There are currently ribozyome  antivirals being developed to treat HIV, and have been proposed for treatment of Hepatitis C.

Protease Inhibitors

Protease Inhibitors work by interfering with the enzymes that catalyze the breaking down (cleaving) of proteins by selectively binding to specific proteases, therefore preventing viral replication. Protease inhibitors were the second class of antiretroviral drugs developed.

Some of the most well-known antivirals used to treat HIV/AIDS and Hepatitis C are protease inhibitors. There are two main classes of protease inhibitors: antiretroviral HIV-1 protease inhibitors (class -navir), and Hepatitis C NS3/4A protease inhibitors (class -previr).

Saquinavir (brand names Invirase, Fortovase) was the first protease inhibitor approved by the FDA in 1995.

Paxlovid (Nirmatrelvir/ritonavir), an antiviral drug used to treat COVID-19, includes nirmatrelvir, a 3C-protease inhibitor that works by targeting coronaviral protease, and ritonvir, which inhibits the metabolism of nirmatrelvir.

Neurominidase Inhibitors

Neurominidase inhibitors prevent the release of influenza viral particles, by blocking an enzyme called neurominidase, which are most notably found on the surface of Influenza viruses. The enzyme cleaves the sialic acid which is found on glycoproteins on the surface of human cells that helps new virions to exit the cell.

Oseltamivir (brand name Tamiflu) works by preventing neuraminidase enzyme activity and thus prevents Influenza A and Influenza B viral particles from being released.

Zanamivir (brand name Relenza) works by binding to the active site of the neuraminidase protein, rendering the influenza virus unable to escape its host cell and infect others.