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‫بسم هللا الرحمن الرحيم‬
MEDICAL MICROBIOLOGY
Chapter 35
Antiviral Drugs
Introduction
the number of antiviral drugs is very small BECAUSE:
1\ the difficulty in obtaining selective toxicity against viruses.
2\ they are relatively ineffective because many cycles of viral
replication occur during the incubation period when the
patient is well .
3\ Another potential limiting factor is the emergence of drug-
resistant viral mutants.
MECHANISM ( SITE) OF ACTION
Table 35–1. Potential Sites for Antiviral Chemotherapy
Site of Action
Effective Drugs
Early events (entry or uncoating
)of the virus
Amantadine, rimantadine, enfuvirtide, maraviroc
Nucleic acid synthesis by viral
DNA and RNA polymerases
Acyclovir, valacyclovir, valganciclovir
Integrase that integrates HIV
DNA into cellular DNA
Raltegravir
Cleavage of precursor
polypeptides
Saquinavir, indinavir, ritonavir, nelfinavir
Protein synthesis directed by
viral mRNA
Interferon, fomivirsen, methisazone
Action of viral regulatory
proteins
None
Assembly of the virus,
including the matrix protein
None
Release of the virus
Zanamivir, oseltamivir
Inhibition of Early Events
adamantanamine
1\adamantanamine, three-ring compound virus
2\It prevents replication by inhibiting uncoating of the virus
3\transcription by the virion RNA polymerase does not because
uncoating cannot occur
4\This drug specifically inhibits influenza A virus; influenza B and C
viruses are not affected
5\it is not widely used in the United States
6\main side effects of amantadine are central nervous system
alterations such as dizziness, ataxia
7\Rimantadine (Flumadine) is a derivative of amantadine and has the
.same mode of action but fewer side effects
Enfuvirtide:
1\ Enfuvirtide is a synthetic peptide that
gp41 on the surface of the virion binds to
2\ block the entry of human
immunodeficiency virus (HIV) into the cell
3\It is the first of a new class of anti-HIV
drugs known as "fusion inhibitors
Inhibition of Viral Nucleic Acid Synthesis
1-Inhibitors of Herpesviruses
* Nucleoside Inhibitors
1\These drugs are analogues of nucleosides
2\inhibit the DNA polymerase of one or more members of the herpesvirus family.
Acyclovir
1\ Acyclovir (acycloguanosine, Zovirax) is a guanosine analogue that has a threecarbon.
2\ Acyclovir is active primarily against HSV-1 and -2 and varicella-zoster virus
(VZV).
3\ it is activated preferentially within virus-infected cells. This is due to the virusencoded thymidine kinase, which phosphorylates acyclovir much more
effectively than does the cellular thymidine kinase
4\ cellular kinases synthesize acyclovir triphosphate, which inhibits viral DNA
polymerase much more effectively than it inhibits cellular DNA polymerase.
5\Acyclovir causes chain termination because it lacks a hydroxyl group in the 3'
position.
6\ It has no activity against CMV.
Figure 35–2
It has selective action because
1\Acyclovir is phosphorylated to acyclovir monophosphate much more
effectively by herpesvirus-encoded thymidine kinase than by cellular
thymidine kinase.
preferentially activated in herpesvirus-infected cells and much less so in
uninfected cells.
2\Acyclovir triphosphate inhibits herpesvirus-encoded DNA polymerase
much more effectively than it does cellular DNA polymerase.
inhibits viral DNA synthesis to a much greater extent than cellular DNA
synthesis
Indication
1\ Topical acyclovir is effective in the treatment of primary
genital herpes and reduces the frequency of recurrences
while it is being taken
2\ Acyclovir is the treatment of choice for HSV-1
encephalitis
3\ effective in preventing systemic infection by HSV-1 or
VZV in immunocompromised patients
Notes:
- Acyclovir-resistant mutants have been isolated from
HSV-1- and VZV-infected patients. Resistance is most
often due to mutations in the gene encoding the viral
thymidine kinase.
cont
-Acyclovir is well-tolerated and causes few side effects
-Intravenous acyclovir may cause renal or central nervous
system toxicity
-Derivatives of acyclovir with various properties are now
available
1-Valacyclovir (Valtrex) achieves a high plasma
concentration when taken orally
2- Penciclovir cream (Denavir) is used in the treatment of
recurrent orolabial herpes simplex
3-Famciclovir (Famvir) when taken orally is converted to
penciclovir and is used to treat herpes zoster and in
herpes simplex infections
Ganciclovir
1\Gancicloviris a nucleoside analogue of
guanosine with a four-carbon fragment
2\It is structurally similar to acyclovir but is more
active against CMV than is acyclovir
3\ Ganciclovir is activated by a CMV-encoded
phosphokinase in a process similar to that by
which HSV activates acyclovir
Indication
1\drug of choice in the treatment of retinitis caused by CMV
in AIDS patients
2\may be useful in other disseminated infections, such as
colitis and esophagitis
Side effect
bone marrow suppression
leukopenia and thrombocytopenia
note\ Valganciclovir, which can be taken orally, is also
effective against CMV retinitis
Cidofovir
1\ Cidofovir is a nucleoside analogue of cytosine
that lacks a ribose ring
Indication
1\ treatment of retinitis caused by CMV
2\ in severe human papillomavirus infections
3\ treatment of severe molluscum contagiosum in
immunocompromised patients
.Note\ Kidney damage is the main side effect
Vidarabine
1\Vidarabine is a nucleoside analogue with arabinose in
place of the normal sugar, ribose.
.
2\the drug is phosphorylated by cellular kinases to the
triphosphate.
inhibits the herpesvirus-encoded DNA polymerase more
effectively than the cellular DNA polymerase
3\Vidarabine is effective against HSV-1 infections such as
encephalitis and keratitis.
Note \ it is less effective and more toxic than acyclovir.
Iododeoxyuridine
1\ Iododeoxyuridine (idoxuridine, IDU, IUDR) is a nucleoside analogue in which
the methyl group of thymidine is replaced by an iodine atom
2\ The drug is phosphorylated to the triphosphate by cellular kinases and
incorporated into DNA
3\It is clinically useful in the topical treatment of keratoconjunctivitis caused by
herpes simplex virus
Note \Because IDU has a high frequency of mismatched pairing to guanine, it
causes the formation of faulty progeny DNA and mRNA
IDU is incorporated into normal cell DNA as well as viral DNA
it is too toxic to be used systemically
Trifluorothymidine
1\ Trifluorothymidine (trifluridine, Viroptic) is a
nucleoside analogue in which the methyl group
of thymidine contains three fluorine atoms
instead of three hydrogen atoms
2\ Its mechanism of action is probably similar to
that of IDU
3\ it is too toxic for systemic use but is clinically
useful in the topical treatment of
keratoconjunctivitis ( drug of choice) caused by
herpes simplex virus
* Non-Nucleoside Inhibitors
These drugs inhibit the DNA polymerase of
herpesviruses by mechanisms distinct from the
nucleoside analogues described above.
Foscarnet
1\ Foscarnet M,unlike the previous drugs which are nucleoside
analogues, is a pyrophosphate analogue
2\ 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.
3\ Foscarnet inhibits the DNA polymerases of all herpesviruses,
especially HSV and CMV.
4\ it does not require activation by thymidine kinase. Foscarnet also
inhibits the reverse transcriptase of HIV
Indication
1\It is useful in the treatment of retinitis
caused by CMV
2\ Foscarnet is also used to treat patients
infected with acyclovir-resistant mutants of
HSV-1 and VZV.
2\Inhibitors of Retroviruses
* Nucleoside Inhibitors
The selective toxicity of (azidothymidine, dideoxyinosine,
dideoxycytidine, d4T, and 3TC) is 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. The
effect of these drugs on the replication of HIV is depicted
in Figure 45–3.
Azidothymidine
1\ Azidothymidine (zidovudine, Retrovir, AZT) is a
nucleoside analogue that causes chain termination
during DNA synthesis
2\ It is particularly effective against DNA synthesis by the
reverse transcriptase of HIV and inhibits growth of the
virus in cell culture.
3\ It is currently the drug of choice in patients with AIDS
Note\ The main side effects of AZT are bone
marrow suppression and myopathy.
Dideoxyinosine
1\ Dideoxyinosine (didanosine, Videx, ddI) is a nucleoside analogue
that causes chain termination during DNA synthesis
2\ The administered drug ddI is metabolized to ddATP, which is the
active compound
3/ 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 AZT
Note/ The main side effects of ddI are pancreatitis and peripheral
neuropathy.
* Dideoxycytidine like Dideoxyinosine
Stavudine
1/ Stavudine (d4T, Zerit) is a nucleoside analogue
that causes chain termination during DNA
synthesis.
2/ 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
Note/ The main side effect is peripheral
neuropathy
Lamivudine
1/ Lamivudine (3TC, Epivir) is a nucleoside analogue that
causes chain termination during DNA synthesis by the
reverse transcriptase of HIV
2/ When used in combination with AZT, it is very effective
both in reducing the viral load and in elevating the CD4
cell count.
3/ Lamivudine is also used in the treatment of chronic
hepatitis B.
Note/
*It is one of the best-tolerated of the nucleoside inhibitors
*side effects such as neutropenia, pancreatitis, and
peripheral neuropathy do occur.
Abacavir
1/ Abacavir (Ziagen) is a nucleoside analogue of
guanosine that causes chain termination during
DNA synthesis.
2/ Abacavir is used in combination with either a
protease inhibitor or AZT plus lamivudine.
Note/ It is available through the "expanded access"
program to those who have failed currently
available drug regimens
Tenofovir
1/ Tenofovir (Viread) is an acyclic nucleoside
phosphonate that is an analogue of adenosine
monophosphate. It is a reverse transcriptase
inhibitor that acts by chain termination
2/ It should be used in combination with other antiHIV drugs.
Note / 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
* Non-Nucleoside Inhibitors
1\ the drugs in this group are not nucleoside analogues and
do not cause chain termination.
2\ act by binding near the active site of the reverse
transcriptase and inducing a conformational change that
inhibits the synthesis of viral DNA.
3\ NNRTIs should not be used as monotherapy because
resistant mutants emerge rapidly.
4\ Strains of HIV resistant to one NNRTI are usually
resistant to others as wel.
Nevirapine(dipyridodiazepinones)
1\ Nevirapine (Viramune) is usually used in
combination with zidovudine and didanosine
2\ There is no cross-resistance with the nucleoside
inhibitors of reverse transcriptase described
above
3\ The main side effect of nevirapine is a severe
skin rash
(Stevens-Johnson syndrome)
( Delavirdine bisheteroarylpiperazines)
1\ Delavirdine (Rescriptor) is effective in
combination with either zidovudine or zidovudine
plus didanosine
Efavirenz(benzoxazin-2-ones )
1\Efavirenz (Sustiva) in combination with
zidovudine plus lamivudine was more effective
and better tolerated than the combination of
indinavir, zidovudine, and lamivudine
2\The most common side effects are referable to
the central nervous system, such as dizziness,
. insomnia, and headaches
Tank you