Download Control of viral Infections

Antiviral Agents
Introduction

Because viruses are obligate intracellular parasites,
identification of safe and effective antiviral therapies is
difficult.

The best antiviral drugs inhibit a specific step in viral
replication or pathogenesis.

Drug discovery can be accomplished by screening or
rational design.

The emergence of virus mutants resistant to antiviral
drugs is a serious problem.

Combination of targeted delivery strategies to control
toxicities and resistance.
Drug Discovery/Development Pipeline
• Multifaceted, complicated, lengthy process
Today's Focus
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Exploratory Development Full Development
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Drug
The pathway for drug discovery
Drug Development

Viruses are now becoming better understood and
several viral genomes have been properly mapped.

Scientists are now looking for the best drug targets

The main point of interest is any viral protein that the
host organism does not normally produce

Once these viral proteins are identified they are tested
using a large scale screening process to test for
effectiveness
Drug Development

Antiviral candidates are tested in mass quantities

Antiviral drugs generally have strange side effects and
a high toxicity

As with any pathogenic agent, Viruses evolve and
develop resistance.

Thus the need for new drugs always exists
Drug Development
There are several known methods that the makers of
Antiviral drugs are looking at, including:
 Prevention of Viral Entry
 Targeting the RNA/DNA replication in the cell
 Targeting the transcriptase factors for Viral DNA
 Destroying Viral proteases so that viral proteins are
not cut and rearranged in optimal order
 Stopping the release of the mature viruses from the
host cell

The development of antiviral agents lagged
significantly behind the development of
antibacterial drugs.

Early drugs were highly toxic.

Analysis of the steps of viral replication has
identified potential targets for antiviral drugs (e.g.
structures, enzymes or processes).

Inhibitors of Attachment include anti-receptor
antibody, natural ligands and synthetic ligands.

Inhibitors of Penetration and uncoating

Amantadine and Rimantadine:-

They are hydrophobic amines (weak organic bases)
with clinical efficacy against influenza A only.

They concentrate in and buffer the contents of the
endosomal vesicles preventing uncoating.

Their specificity stems from their ability to bind to
and block the proton channel formed by the M2
matrix protein.
Influenza Treatment with Ion Channel
Blockers Amantadine & Rimantadine

Prevent seasonal influenza A in 70-80% of cases

Can reduce severity & duration of illness if started
within 48 hrs of onset of symptoms.

Treated persons may shed resistant virus after 5-7
days of treatment (sometimes as early as 2-3
days). All pandemic H1N1 strains are resistant.

Treatment should be discontinued after 3-5 days
of treatment or within 24-48 hrs after
disappearance of signs/symptoms).
Pleconaril
 It is a broad spectrum antipicorna virus agent.


It is a small cyclic drug which binds to a canyon pore
of the virus.

In doing so it blocks attachment and uncoating of the
viral particle.

It is orally bioavailable and can reduce peak viral titers
by more than 99%.

Inhibitors of Genome Replication

Many viruses have evolved their own specific
enzymatic mechanisms to preferentially replicate
virus nucleic acids at the expense of cellular
molecules.

There is often sufficient specificity in virus
polymerases to provide a target for a specific
antiviral agent and this method has produced the
majority of the specific antiviral agents currently in
use.

The majority of these drugs function as polymerase
substrate, i.e. nucleoside analogues.

Toxicity varies considerably.

There is a serious problem with the pharmacokinetics of
these nucleoside analogues (typically short serum half
lives of 1-4 hours).

Nucleoside analogues are in fact pro-drugs, since they
need to be phosphorylated before becoming effective.
This is the key to their selectivity.
Nucleoside Analogues

Acyclovir (acycloguanosine )- ACV.
Close to a perfect antiviral drug (specific, nontoxic).

Highly effective against herpes simplex virus (HSV), less
so against varicella -zoster virus (VZV).

Highly selective and extremely safe.

Acyclic guanine derivative (differs from guanosine by
having an acyclic side chain) that inhibits viral DNA
synthesis.
Antiviral Drugs
Nucleoside and Nucleotide Analogs
Figure 20.16a

It is a prodrug, a precursor of the antiviral compound.

Activation of the drug requires three kinase activities to
be present in the cell to convert acyclovir to a
triphosphate derivative, the actual antiviral drug.
 It is phosphorylated by a virus thymidine kinase (200
times more efficiently than by cellular enzymes)
producing a monophosphate form.
 Cellular enzymes complete phosphorylation to the di and triphosphate forms.
 The triphosphorylated form competes with GTP
inhibiting the enzyme (DNA polymerase) and
causing termination of the growing viral DNA
chain because of lack of 3' OH group.
 ACV affinity to viral polymerase is more than 100
folds that to cellular polymerase.

Acyclovir has no effect on host DNA replication
because the first kinase activity is not found in an
noninfected cell.
Antiviral Drugs
Nucleoside and Nucleotide Analogs
 Valacyclovir
o the valyl ester derivative of ACV is more efficiently absorbed
and rapidly converted to ACV increasing its bioavailability.
o Penciclovir and famciclovir are related drugs.
 Ganciclovir
o It differs from ACV by the addition of a single hydroxymethyl
group in the acyclic side chain; the result is a remarkable
activity against CMV.
o It is phosphorylated by a virus-encoded kinase (not thymidine
kinase).
 Adenine arabinoside (vidarabine)- Ara -A
o A purine analogue (identical to adenosine but
arabinose is substituted for ribose).
o Phosphorylated by cellular enzymes ( toxicity?) to
inhibit both viral and cellular polymerases but viral is
6-12 times more sensitive.
o It was used for HSV and VZV before ACV.
Azidothymidine (Zidovudine) AZT


Dideoxy analog of
thymidine
(a synthetic thymidine
analogue) that Inhibits
viral DNA synthesis by
inhibiting the reverse
transcriptase enzyme.
It has higher affinity to
RT (100 times) than to
cellular DNA polymerase.

Efficiently phosphorylated (several steps of
phosphorylation) to triphosphate by cellular
kinases

AZT monophosphate competes with thymidine
monophosphate

Much less selective than acylovir and has side
effects

Does not eliminate previously incorporated
provirus
 Dideoxyinosine (Didanosine, ddI)
 Dideoxycytidine (Zalcitabine, ddc)
 Stavudine (d4t)
 Lamivudine (3Tc).
o All are inhibitors of reverse transcriptase used for the treatment
of HIV infection.

Ribavarin
o An analogue of guanosine but the base ring is incomplete and
open.
o It is active against DNA and RNA viruses by inhibiting inosine
monophosphate dehydrogenase and the synthesis of the mRNA
5- cap and RNA polymerase.



Iododeoxyuridine (Idoxyuridine)
Trifluorothymidine (Trifluridine)
Fluorouracil
o All are analogues of thymidine and they inhibit the
biosynthesis of thymidine or replace it and become
incorporated in DNA.

Nucleotide Analogue (cidofovir)
o It has the phosphate group attached and it inhibits
DNA polymerase .
Nonnucleoside polymerase Inhibitors


Foscarnet: anti-herpes viruses.
Nevirapine and delaviridine : anti HIV
 Protease Inhibitors

Anti HIV: Saquinavir, Indinavir, and Ritonavir
o Anti HCV: Boceprevir and Telaprevir
o The Unique structure of HIV protease and its essential role in
the production of a functional virion has made this enzyme a
good target for antiviral drugs.

Uncleavable mimics of gag- pol polyprotein

Inhibits HIV protease

Does not eliminate previously incorporated
provirus but does prevent further spread

Resistance due to protease alterations
Inhibitors of Assembly, Maturation and Release
 Zanamivir/ Relenza (aerosol)
 Oseltamivir / Tamiflu (tables)

Peramivir/ IV for emergency use in hospitalized adults or children
o Active against influenza as they are inhibitors of
neuraminidase preventing the release of budded viruses from
the cell.
o Because they act late in the life cycle of the virus it is hoped
that problems with resistance emergence will be minimized.
Neuraminidase Inhibitors Zanamivir &
Oseltamivir

Mechanism: blocking of the active site of neuraminidase;
prevents removal of sialic acid residues and results in
clumping of viral progeny

Effective against influenza A & B.

Effective when flu symptoms are < 2 days old.

Inhibitors reduce disease syndrome by 1 day.

May decrease influenza secondary complications

Antiviral resistance can occur, but much less frequently
than with the ion channel blockers amantadine or
rimantadine

Neuraminidase inhibitors appear to have similar
efficacy to the amantidine & rimantidine ion
channel blockers for prevention & treatment of
influenza

Neuraminidase inhibitors have Less Central
Nerveous System side effects, but more GastroIntestinal effects

Neuraminidase Inhibitors are more expensive, but
there is less risk of inducing virus resistance.
 Methisazone
o It is of historical importance as an inhibitor of
poxviruses.
o It was highly virus specific and did not affect cellular
metabolism.
o It blocked a late stage in viral replication resulting in
the formation of immature, noninfectious virus
particles.