ANTIVIRAL DRUGS

Dian Rachma Wijayanti M.Sc

PALMK-4, SEMESTER GANJIL 2021/2022
PRINCIPLES OF ANTIVIRAL THERAPY
• Compared with the number of drugs available to treat bacterial infections, the number of antiviral
drugs is very small.
• The major reason for this difference is the difficulty in obtaining selective toxicity against viruses; their
replication is intimately involved with the normal synthetic processes of the cell.

• Another limitation of antiviral drugs is that they are relatively ineffective because many cycles of viral
replication occur during the incubation period when the patient is well. By the time the patient has a
recognizable systemic viral disease, the virus has spread throughout the body and it is too late to
interdict it.
• Furthermore, some viruses (e.g., herpesviruses) become latent within cells, and no current antiviral drug
can eradicate them.

• Another limiting factor is the emergence of drug-resistant viral mutants. For example, when drug-
resistant mutants of HIV emerge, it requires that drug regimens be changed. Also, treatment of HIV
infection uses multiple drugs, often from different classes, so that if mutants resistant to one drug
emerge, another drug will still be effective
Levinston WE, et al. 2018
 TARGETS FOR ANTIVIRAL DRUGS
• The different targets for Levinston W, et al. 2018
Levinston WE, et al. 2018
antiviral drugs are
structures, enzymes, or
processes important or
essential for virus
production etc.
• These targets are
spesiffic and essential
to optimize antiviral
drugs effect.
Murray, et al. 2020
 Levinston WE, et al. 2018
Sebagian besar obat antivirus menghambat tahapan pada saat replikasi virus : Tahapan awal virus masuk ke sel
inang, sintesis asam nukleat, sintesis protein, sampai pelepasan virion dari sel terinfeksi virus.
 Amantadine
INHIBITION OF • Rimantadine Enfuvirtide

EARLY EVENTS
(ENTRY OR Maraviroc Palivizumab
UNCOATING OF VIRUS)
AMANTADINE

• Amantadine (α-adamantanamine, Symmetrel) is a three-ring compound that blocks the

replication of influenza A virus. It prevents replication by inhibiting uncoating of the virus
by blocking the “ion channel” activity of the matrix protein (M2 protein) in the virion.
• Absorption and penetration occur normally, but transcription by the virion RNA polymerase
does not because uncoating cannot occur.
• This drug specifically inhibits influenza A virus; influenza B and C viruses are not affected.
Despite its efficacy in preventing influenza, it is not widely used in the United States because
the vaccine is preferred for the high-risk population.
• Furthermore, most isolates have become resistant to amantadine. The main side effects of
amantadine are central nervous system alterations such as dizziness, ataxia, and insomnia.
• Rimantadine (Flumadine) is a derivative of amantadine and has the same mode of action but
fewer side effects
ENFUVIRTIDE, MARAVIROC DAN PALIVIZUMAB

• Enfuvirtide (Fuzeon) is a synthetic peptide that binds to gp41 on the surface of HIV, thereby
blocking the entry of the virus into the cell. It is the first of a new class of anti-HIV drugs
known as “fusion inhibitors” (i.e., they prevent the fusion of the viral envelope with the cell
membrane)
• Maraviroc (Selzentry) blocks the binding of HIV to CCR-5—an important coreceptor for those
strains of HIV that use CCR-5 for entry into the cell. The drug binds to CCR-5 and blocks the
interaction of gp120, an HIV envelope protein, to CCR-5 on the cell surface.
• Palivizumab (Synagis) is a monoclonal antibody directed against the fusion protein of
respiratory syncytial virus (RSV). Palivizumab neutralizes RSV by binding to the fusion protein
on the surface of RSV, thereby preventing the virus from binding to receptors on the surface of
respiratory tract mucosal cells. It is used to prevent bronchiolitis and pneumonia in premature
or immunocompromised infants
INHIBITION OF VIRAL
NUCLEIC
ACID SYNTHESIS
INHIBITORS OF HERPESVIRUSES

• Nucleoside Inhibitors
These drugs are analogues of nucleosides that inhibit the DNA polymerase of
one or more members of the herpesvirus family.
• Nonnucleoside Inhibitors
Nonnucleoside inhibitors inhibit the DNA polymerase of herpesviruses by
mechanisms distinct from the nucleoside analogues described previously.
Foscarnet is the only approved drug in this class at this time.
INHIBITORS OF HERPESVIRUSES
NUCLEOSIDE INHIBITORS
1. Acyclovir—Acyclovir (acycloguanosine, Zovirax) is a guanosine analogue that has a
three-carbon fragment in place of the normal sugar, ribose, which has five carbons. The
term acyclo refers to the fact that the three-carbon fragment does not have a sugar ring
structure (a = without, cyclo = ring).
1. Acyclovir is active primarily against HSV-1 and -2 and varicella-zoster virus (VZV). It is relatively
nontoxic, because it is activated preferentially within virus-infected cells.
2. Ganciclovir—Ganciclovir (dihydroxypropoxymethylguanine, DHPG, Cytovene) is a
nucleoside analogue of guanosine with a four-carbon fragment in place of the normal
sugar, ribose. It is structurally similar to acyclovir but is more active against cytomegalovirus
(CMV) than is acyclovir.
1. Ganciclovir is activated by a CMV-encoded phosphokinase in a process similar to that by which
acyclovir is activated by HSV. Isolates of CMV resistant to ganciclovir have emerged, mostly due to
mutations in the UL97 gene that encodes the phosphokinase.
Levinston WE, et al. 2018
INHIBITORS OF HERPESVIRUSES
NUCLEOSIDE INHIBITORS (2)
3. Cidofovir—Cidofovir (hydroxyphosphonylmethoxypropylcytosine, HPMPC, Vistide) is an analogue of
cytosine that lacks a ribose ring. Cidofovir does not have to be phosphorylated and therefore is not
dependent on the action of a virus-encoded phosphokinase.
• It is useful in the treatment of retinitis caused by CMV and in severe human papillomavirus
infections. It may be useful in the treatment of severe molluscum contagiosum in
immunocompromised patients. Kidney damage is the main side effect
4. Trifluridine—(trifluorothymidine, Viroptic) is a nucleoside analogue in which the methyl group of
thymidine contains three fluorine atoms instead of three hydrogen atoms. The drug is phosphorylated to
the triphosphate by cellular kinases and incorporated into DNA. Because it has a high frequency of
mismatched pairing to adenine, it causes the formation of faulty progeny DNA and mRNA.
• However, because it is incorporated into normal cell DNA as well as viral DNA, it is too toxic to be
used systemically. It is the drug of choice for the topical treatment of keratoconjunctivitis caused by
herpes simplex virus.
INHIBITORS OF HERPESVIRUSES
NONNUCLEOSIDE INHIBITORS
4. Foscarnet—Foscarnet (trisodium phosphonoformate, Foscavir), unlike the previous
drugs, which are nucleoside analogues, is a pyrophosphate analogue.
• It binds to DNA polymerase at the pyrophosphate cleavage site and prevents removal of the
phosphates from nucleoside triphosphates (dNTP). This inhibits the addition of the next dNTP
and, as a consequence, the extension of the DNA strand.

• Foscarnet inhibits the DNA polymerases of all herpesviruses, especially HSV and
CMV. Unlike acyclovir, it does not require activation by thymidine kinase. It is useful
in the treatment of retinitis caused by CMV, but ganciclovir is the drug of first
choice for this disease.
• Foscarnet is also used to treat patients infected with acyclovir-resistant mutants of HSV-1
and VZV.
INHIBITORS OF HUMAN IMMUNODEFICIENCY VIRUS

• Nucleoside Inhibitors
The selective toxicity of nucleoside inhibitors are based on their ability to inhibit DNA synthesis
by the reverse transcriptase of HIV to a much greater extent than they inhibit DNA synthesis by
the DNA polymerase in human cells.
• Thesedrugs are collectively called nucleoside reverse transcriptase inhibitors (NRTIs).

• Nonnucleoside Inhibitors
The drugs in this group are not nucleoside analogues and do not cause chain termination. The
nonnucleoside reverse transcriptase inhibitors (NNRTIs) act by binding near the active site of
the reverse transcriptase and inducing a conformational change that inhibits the synthesis of
viral DNA.
• NNRTIs should not be used as monotherapy because resistant mutants emerge rapidly. Strains of
HIV resistant to one NNRTI are usually resistant to others as well. NNRTIs are typically used in
combination with one or two nucleoside analogues.
INHIBITORS OF HUMAN IMMUNODEFICIENCY VIRUS
NUCLEOSIDE INHIBITORS
1. Zidovudine—Zidovudine (azidothymidine, Retrovir, AZT) is a nucleoside analogue that causes chain
termination during DNA synthesis; it has an azido group in place of the hydroxyl group on the
ribose. It is particularly effective against DNA synthesis by the reverse transcriptase of HIV and
inhibits the growth of the virus in cell culture. The main adverse effects of zidovudine are bone
marrow suppression and myopathy.
2. Lamivudine—Lamivudine (dideoxythiacytidine, Epivir,3TC) is a nucleoside analogue that causes
chain termination during DNA synthesis by the reverse transcriptase of HIV. When used in
combination with AZT, it is very effective both in reducing the viral load and in elevating the CD4 cell
count.
• Lamivudine is also used in the treatment of chronic hepatitis B because it inhibits the reverse
transcriptase of hepatitis B virus. It is one of the best tolerated of the nucleoside inhibitors, but
adverse effects such as neutropenia, pancreatitis, and peripheral neuropathy do occur.
3. Emtricitabine—Emtricitabine (Emtriva), a derivative of lamivudine, is also useful and well tolerated
INHIBITORS OF HUMAN IMMUNODEFICIENCY VIRUS
NUCLEOSIDE INHIBITORS
4. Didanosine—Didanosine (dideoxyinosine, ddI, Videx) is a nucleoside analogue that causes chain
termination during DNA synthesis; it is missing hydroxyl groups on the ribose. The administered drug
ddI is metabolized to ddATP, which is the active compound. It is effective against DNA synthesis by the
reverse transcriptase of HIV and is used to treat patients with AIDS who are intolerant of or resistant to
zidovudine. The main adverse effects of didanosine are pancreatitis and peripheral neuropathy.
5. Stavudine—Stavudine (didehydrodideoxythymidine, d4T, Zerit) is a nucleoside analogue that causes
chain termination during DNA synthesis. It inhibits DNA synthesis by the reverse transcriptase of HIV
and is used to treat patients with advanced AIDS who are intolerant of or resistant to other approved
therapies. The main adverse effect is peripheral neuropathy.

6. Abacavir—Abacavir (Ziagen) is a nucleoside analogue of guanosine that causes chain termination

during DNA synthesis. It is available through the “expanded access” program to those who have
failed currently available drug regimens. Abacavir is used in combination with either a protease
inhibitor, typically darunavir and ritonavir, or zidovudine plus lamivudine.
INHIBITORS OF HUMAN IMMUNODEFICIENCY VIRUS
NUCLEOSIDE INHIBITORS

7. Tenofovir—Tenofovir (Viread) is an acyclic phosphonate that is an analogue

of adenosine monophosphate. It is a reverse transcriptase inhibitor that acts by
chain termination.
• It is approved for use in patients who have developed resistance to other reverse
transcriptase inhibitors and in those who are starting treatment for the first time.
• It should be used in combination with other anti-HIV drugs. The main adverse effects are
liver damage, lactic acidosis, and renal failure.
INHIBITORS OF HUMAN IMMUNODEFICIENCY VIRUS
NONNUCLEOSIDE INHIBITORS

1. Nevirapine—Nevirapine (Viramune) is usually used in combination with zidovudine and didanosine.

There is no cross-resistance with the nucleoside inhibitors of reverse transcriptase described previously. The
main side effect of nevirapine is a severe skin rash (Stevens-Johnson syndrome).
2. Delavirdine—Delavirdine (Rescriptor) is effective in combination with either zidovudine or
zidovudine plus didanosine. The main side effect of delavirdine is a skin rash.
3. Efavirenz—Efavirenz (Sustiva) is effective in combination with zidovudine plus lamivudine. The most
common side effects are referable to the central nervous system, such as dizziness, insomnia, and
headaches.
4. Etravirine—Etravirine (Intelence) is a second-generation NNRTI useful in treatment-experienced
patients who have significant viremia.The most common adverse effect is a rash, and StevensJohnson
syndrome has occurred, albeit rarely.
5. Rilpivirine—Rilpivirine (Edurant) is a second-generation NNRTI useful in treatment-naïve adult
patients. It is most effective when used in combination with either tenofovir or emtricitabine. The most
common adverse effects are depression and insomnia.
INHIBITORS OF HEPATITIS B VIRUS
1. Adefovir
Adefovir (Hepsera) is a nucleotide analogue of adenosine monophosphate that inhibits the DNA
polymerase (reverse transcriptase) of hepatitis B virus (HBV). It is used for the treatment of chronic
active hepatitis caused by this virus.
2. Entecavir
Entecavir (Baraclude) is a guanosine analogue that inhibits the DNA polymerase (reverse transcriptase)
of HBV. It has no activity against the DNA polymerase (reverse transcriptase) of HIV. It is approved for
the treatment of adults with chronic HBV infection.
3. Telbivudine
Telbivudine (Tyzeka) is a thymidine analogue that inhibits the DNA polymerase (reverse transcriptase)
of HBV but has no effect on the reverse transcriptase of HIV. It is useful in the treatment of chronic
HBV infection.
4. Lamivudine & Tenofovir
Mechanisme is the same in retrovirus, HIV.
.”
INHIBITORS OF HEPATITIS C VIRUS

1. RNA polymerase inhibitors

• Sofosbuvir
Sofosbuvir (Sovaldi) is a uridine analogue that inhibits the RNA polymerase of
HCV. It acts as a chain terminating drug. It is useful in the treatment of chronic
HCV infection caused by genotypes 1, 2, 3, and 4.
• Dasabuvir
Dasabuvir is a nonnucleoside inhibitor of the RNA polymerase of HCV. Its precise
mode of action is uncertain as of this writing. It is available in combination with
ombitasvir (an NS5A inhibitor), paritaprevir (a protease inhibitor), and ritonavir (a
booster of protease inhibitor activity). This four-drug combination is called Viekira.
INHIBITORS OF HEPATITIS C VIRUS (2)

2. NS5A inhibitors
• Ledipasvir
Ledipasvir is an inhibitor of NS5A, an RNA-binding protein required for the activity
of the RNA polymerase of HCV. Ledipasvir is available in combination with
sofosbuvir (Harvoni) and is useful in the treatment of chronic HCV infection caused by
genotype 1.
• Ombitasvir
Ombitasvir is another NS5A inhibitor that is available in combination with dasabuvir
(a polymerase inhibitor), paritaprevir (a protease inhibitor), and ritonavir (a booster
of protease inhibitor activity). This four-drug combination is called Viekira
INHIBITION OF INTEGRASE
AND PROTEASE
INHIBITION OF INTEGRASE

• Raltegravir (Isentress) is an integrase inhibitor

• i.e., it blocks the HIV-encoded integrase that mediates the integration of the
newly synthesized viral DNA into host cell DNA.
• Two additional integrase inhibitors are available: dolutegravir (Tivicay)
and elvitegravir (Stribild).
INHIBITION OF PROTEASE-HIV

• Members of the protease inhibitor (PI) class of drugs, such as

• Saquinavir (Invirase, Fortovase),
• Indinavir (Crixivan),
• Ritonavir (Norvir),
• Lopinavir/Ritonavir (Kaletra),
• Atazanavir (Reyataz),
• Tipranavir (Aptivus),
• Amprenavir (Agenerase) and its prodrug Fosamprenavir (Lexiva), Darunavir (Prezista),
and Nelfinavir (Viracept), inhibit the protease encoded by HIV
INHIBITION OF PROTEASE-HCV

• Boceprevir (Victrelis), simeprevir (Olysio), telaprevir (Incivek), and paritaprevir

(component of Viekira) are PIs that block a serine protease required for the
replication of hepatitis C virus.
• They are approved for the treatment of chronic hepatitis C caused by hepatitis C
virus (genotype 1) in combination with peginterferon and ribavirin. The most
important adverse effect of these drugs is anemia.
• Paritaprevir is an inhibitor of HCV protease that is available in combination
with ombitasvir (an NS5A inhibitor), dasabuvir (a polymerase inhibitor), and ritonavir
(a booster of PI activity). This fourdrug combination is called Viekira.
 INHIBITION OF VIRAL
PROTEIN SYNTHESIS, RELEASE OF VIRUS
& CHEMOPROPHYLAXIS
INHIBITION OF VIRAL PROTEIN SYNTHESIS

• Interferon
Recombinant alpha interferon is effective in the treatment of some patients
with chronic hepatitis B and chronic hepatitis C infections.
• Note that the use of alpha interferon and pegylatedalpha interferon for
chronic HCV infection has been significantly reduced due to the availability of
newer less toxic drug regimens.
• Alpha interferon also causes regression of condylomata acuminata lesions
caused by human papillomavirus and the lesions of Kaposi’s sarcoma caused
by human herpesvirus-8.
INHIBITION OF VIRAL PROTEIN SYNTHESIS

• Fomivirsen
Fomivirsen (Vitravene) is an antisense DNA that blocks the replication of CMV.
• Antisense DNA is a single-stranded DNA whose base sequence is the
complement of the viral mRNA. Antisense DNA binds to the mRNA within
the infected cell and prevents it from being translated into viral protein.
• Fomivirsen is approved for the intraocular treatment of CMV retinitis. It
is the first and, at present, the only antisense molecule to be approved for the
treatment of human disease.
INHIBITION OF RELEASE OF VIRUS

• Oseltamivir (Tamiflu), zanamivir (Relenza), and peramivir (Rapivab) inhibit the

neuraminidase of influenza virus.
• This enzyme is located on the surface of influenza virus and is required
for the release of the virus from infected cells.
• Inhibition of release of influenza virus limits the infection by reducing the
spread of virus from one cell to another.
• These drugs are effective against both influenza A and B viruses, in contrast to
amantadine, which is effective only against influenza A virus.
• These drugs are effective against strains of influenza virus resistant to amantadine.
CHEMOPROPHYLAXIS

• In most instances, the antiviral agents are used to treat infectious diseases.
However, there are times when they are used to prevent diseases from
occurring—a process called chemoprophylaxis.
THANK YOU