Lecture 5

Antiviral Agents and Sulfonamides

ANTIVIRAL AGENTS

2
 VIRUSES
• Viruses are cellular parasites composed of nucleic acid,
surrounded by proteinaceous shell. They depend on the
host for energy and replication. They are either single
or double stranded DNA or RNA type. They cause
much mortality especially after AIDS epidemics
• Replication depends on synthetic processes of the host
cell

• Most viruses contain or encode enzymes essential for

viral replication inside a host cell

3
Viral replication consists of several steps :
• I- Early stages
1) attachment
2) penetration
3) uncoating
• II- Replication
1) transcription
2) transition
3) genome replication
• III- Virus assembly
1) capside assembly
2) glycoprotein transport and budding
4
 Antiviral Agents
I) ANTIHERPES VIRUS AGENTS

1) Vidarabine (nucleoside)
• adenosine analogue
• inhibits DNA polymerase activity
through competitive inhibition with
dATP.
• deamination product by adenosine
deaminase is at least 10-fold less
potent
• its toxicities restricted its NH2 O

use to life-threatening infections of N

N
N
NH
HSV and varicella-zoster virus N N
N N
(VZV) HO
O deamination
HO
O
H HO H HO
H H H H
OH H OH H

Vidarabine Ara-HX

5
2) Acyclic nucleoside, Acyclovir (ACV) Guanosine Analogue
• is one of the most important groups of antiherps drugs that
inhibit viral nucleic acid synthesis. They are phosphorylated to
triphosphate that inhibit viral growth by acting as competitive
inhibitor of DNA polymerases ( human enzyme are much less
susceptible)
• ACV is a standard treatment for HSV-1, HSV-2, and varicella-
zoster virus (VZV).

6
 Synthesis:
O
N 1 ) alk y latio n
HN
+ C lC H 2 O C H 2 C H 2 O O C A cyclovir
N 2 ) h y d ro ly sis
H 2N N
H

G u an in e 2 (ch lo ro m eth o xy )eth y l b en zo ate

8
• The relatively low toxicity of (ACV) is due to
a) ACV is an analogue of 2-deoxyguanosine, which must be
activated by conversion to the triphosphate. by the
thymidine kinases.

b) The first phosphorylation results in localization of the

monophosphorylated form to infected cells because the
charged phosphate prevents translocation across the plasma
membrane.

c) ACV is recognized more efficiently by viral than cellular

polymerases.

9
• ACV has a low oral bioavailability (15-30%). Increasing oral
bioavailability of ACV would allow lower or less frequent
doses.
• Acyclovir Prodrugs
Prodrugs for acyclovir are used to improve its poor absorption
after oral administration.
• Valciclovir is the valinyl ester of acyclovir which improves
bioavailability , it is better absorbed.

10
 O O
N N
NH NH
O N N
N NH2 N NH2
HO
O Esterase enzyme
O O
NH2

Valciclovir Acyclovir

Relatively small changes to the acyclic side chain of ACV have

resulted in two additional drugs, ganciclovir (GCV) and
penciclovir (PCV) that differ in their effectiveness against
herpesviruses. GCV is more effective against Human
cytomegalovirus (HCMV) than against HSV or VZV, the
reverse of ACV.
The factors limiting GCV efficacy are its low
bioavailability (< 10%) and its side effect profile.

11
• The prodrug form of GCV, Valganciclovir improves the oral
bioavailability of GCV although it still has the same toxicity
profile.

• Penciclovir shares structural similarity with GCV but is closer

to ACV in its antiviral spectrum. The triphosphorylated form
retains activity against ACV resistant HSV polymerase.
12
• HSV thymidine kinase has a much higher affinity for PCV
than ACV , but the triphosphate form is used about 40-fold
less well by the HSV and VZV polymerases than ACV
triphosphate.

• PCV triphosphate is approximately 10-fold more stable than

ACV triphosphate, such that PCV-triphosphate levels are over
300-fold higher than ACV-triphosphate levels.

• PCV is activated at a low level by cellular kinases. This,

combined with a greater than 4000-fold greater affinity for the
hepatitis B (HBV) polymerase than the cellular polymerase,
makes PCV an inhibitor of HBV replication.
13
• Oral bioavailability of PCV is about 5%; however, an effective
prodrug form, Famciclovir, has been developed.

14
3) Idoxuridine
• Iodinated thymidine analogue that inhibits the in vitro replication
of various DNA viruses, including herpesviruses and poxviruses.
Use : 1% ophthalmic solution in treatment of kerato conjuctivities
( HSV)

Mechanism of action Inhibitor DNA polymerase, inhibition

synthesis of DNA ( DNA containing halogenated pyrimidine)

4) Trifluridine
• It is a fluorinated pyrimidine nucleoside that has in vitro inhibitory
activity against HSV types 1 and 2, Cytomegalovirus (CMV).

• Trifluoridine triphosphate is a competitive inhibitor of thymidine

triphosphate incorporation into DNA.

15
5) Foscarnet sodium
• Foscarnet (trisodium phosphonoformate) is an inorganic
pyrophosphate analogue that inhibits DNA polymerase of
herpes viruses including HIV.

• Foscarnet not phosphorylated into an active form

must be administered intravenously.

• Effectiveness against HCMV is equivalent to GCV, and the

magnitude of side effects is similar. whereas there is no
prodrug from of foscarnet.

16
II) Anti Retroviruses (HIV) Agents
1) Nucleoside reverse transcriptase inhibitors:
• The best known class of the antiretroviral agents containing
seven members – zidovudine, didanosine, zalcitabine,
stavudine, lamivudine, abacavir, and emtricitabine.

2',3'-didehydro-3'-deoxythymidine.
18
19
• All these compounds have in common is that they are 2’,3’-
dideoxynucleoside analogues which through the absence of a
3’-hydroxyl group act as chain terminators at the reverse
transcriptase level.

2) Nucleotide reverse transcriptase inhibitors:

• NtRTIs should be clearly distinguished from the NRTIs as they
contain a phosphonate group that is isosteric with the
phosphate group of the normal nucleotides.

• To this class of compounds belong adefovir and tenofovir.

20
• They are used in their oral prodrug forms, adefovir dipivoxil
and tenofovir disoproxil fumarate (TDF), in the treatment of
hepatitis B virus (HBV) and HIV infections, respectively.

21
3) Nonnucleoside reverse transcriptase inhibitors
• Nonnucleoside reverse transcriptase inhibitors (NNRTIs)
include a variety of chemical substrates that bind to a
hydrophobic pocket in the p66 subunit of the HIV-1 reverse
transcriptase, e.g. nevirapine, etravirine and rilpivirine

22
• noncompetitive inhibitor that binds to a site on the HIV-1
reverse transcriptase that is distant from the active site,
inducing a conformational change that disrupts catalytic
activity. Since the target site is HIV-1-specific and is not
essential for the enzyme, resistance can develop rapidly.

24
4) HIV INTEGRASE INHIBITORS

• In HIV integrase inhibitors, the prime structural determinant is

undoubtedly the diketo acid group.

• Both raltegravir and elvitegravir are assumed to interfere with

the strand transfer reaction of the HIV integrase.
25
III) ANTI-INFLUENZA AGENTS
1) Amantadine and Rimantadine
• Amantadine and rimantadine share two mechanisms of
antiviral action. They inhibit viral uncoating; for some strains,
they also have an effect on viral assembly probably mediated
through altering hemagglutinin processing.

• It has been considered a potential strategy for the therapy and

prophylaxis of influenza A virus infections.

• 1-Adamantamine HCl (Amantadine)

• -Methyl-1-adamantane methyl amine (Rimantadine)

26
2) Neuraminidase inhibitors
• At present, the neuraminidase inhibitors are still considered the
most likely candidates to be used not only to curtail the annual
recurrences of seasonal influenza (A (H1N1), A (H3N2), and
influenza B) but also to prevent pandemics with any influenza
A virus infection, whether avian (i.e., influenza A H5N1) or
any new influenza A (H1N1) strain, such as the recent
Mexican variant.

27
• Neuraminidase inhibitors do have a very specific interaction
with the viral neuraminidases (sialidase), trapping the newly
formed virions.

• Unfortunately, influenza A seems to readily develop resistance

against neuraminidase inhibitors such as oseltamivir.

28
IV) ANTIHEPATITIS AGENTS H H
N
1) Ribavirin Ribavirin
N
1-D-ribofuranosyl-1-H-1,2,4-triazole-3- O

carboxamide. N
N

• It is a purine nucleoside analogue with a HO

O
modified base and D-ribose sugar. H H

• It is adenosine mimic. H
OH
H
OH
• It is active against ( DNA, RNA viruses). H H
• The antiviral mechanism of ribavirin Adenosine
N

is incompletely understood but relates to N

N

alteration of cellular nucleotide pools and N N

inhibition of viral messenger RNA synthesis HO
• Use: lower respiratory infections caused H
O
H
by respiratory syncytical virus (RSV) H
OH
H
OH
Hepatitis C with interferon alfa. 2a
29
 Sofosbuvir

Sofosbuvir is in the nucleotide analog , works

by blocking the hepatitis C NS5B protein.

Nonstructural protein 5B (NS5B) is a viral protein found in the hepatitis

C virus (HCV). It is an RNA polymerase, having the key function of
replicating HCV's viral RNA by using the viral positive RNA strand as a
template to catalyze the polymerization of ribonucleoside triphosphates
(rNTP) during RNA replication.

sofosbuvir can be used in combination with daclatasvir