Transcript Antiviral Drugs.ppt

Viruses
 Viruses
are
sub-microscopic
obligatory
intracellular parasites consisting either of DNA or
RNA and a protein coat.
 They lack both
membrane
and
the cell
do
not
wall
carry
and the
out
cell
metabolic
processes.
 Viruses possess only few or none of the enzymes
involved in replication. Therefore, viruses need a
host cell to utilise its enzymatic activity for their
replication, existence and growth
Classification of viruses
1) DNA viruses : e.g. the adenoviruses that
cause acute respiratory diseases; herpes
simplex, chickenpox and varicella zoster
viruses
2) RNA viruses: e.g. the causative agent of
encephalitis, respiratory illness, influenza,
diarrhoea and AIDS (caused by
retroviruses).
Antiviral chemotherapeutics
 Antiviral
used
in
chemotherapeutics
the
treatment
and
are
substances
prophylaxis
of
diseases caused by viruses.
 The primary indications for the use of antiviral
drugs
in
ophthalmology
are
viral
keratitis,
herpes zoster ophthalmicus, and retinitis Viral
conjunctivitis caused by adenoviruses
 The action of antiviral agents might involve the
penetration and uncoating or any other process
in the replication of the virus.
Replication of a virus
Tricyclic amines
(Adamantane derivatives)
Amantadine, Rimantadine,
Somantadine and Tromantadine
Amantadine
.HCl
NH2
• Adamantane derivatives are
uniquely configured tricyclic
amines.
• They are useful for prevention
but not treatment of influenza
1-Adamantanamine
caused by influenza A virus.
hydrochloride
The mode of action:
appears to involve the inhibition of uncoating of the
RNA virus; thereby blocking the transfer of viral
RNA into the host cell. It may also involve
prevention of penetrations of the intact virus into
the host cell
Nucleoside
analogues
They have close structural similarity with the natural
metabolites.
They are designed via structural modification of
these natural metabolites
They interfere with the normal metabolic processes
and/or inhibit the enzymes involved in these
processes.
considered as bioprecursor pordrugs as they have to
be activated in vivo.
They should be phosphorylated inside infected cell.
The main mechanism of action involve inhibition of
the viral DNA synthesis, by inhibiting DNA polymerase
or by incorporating itself into the DNA chain,
impairing its elongation.
They can be seen chemically as either pyrimidine or
purine analogues
A) Pyrimidine nucleoside
analogues
1) Trifluridine (Viroptic)
O
CF 3
HN
O
N
O
HO
HO
 -Trifluorothymidine;
2`-Deoxy-5-(trifluoromethyl)-uridine
• It has a very close structural similarity with the natural
metabolite thymidine
• Trifluridine is only active against DNA viruses such as
herpes.
• It is used as 1% sterile solution ophthalmic to treat keratoconjunctivitis caused by herpes simplex (HSV).
Mechanism of action
Viral thymidylate
Monophosphate
Trifluridine
kinase
Cellular kinases
Triphosphate
(an inhibitor and a substrate of
viral DNA polymerase)
Strand breakage
Inhibition of viral DNA synthesis
and producing false DNA
miscode errors in RNA
and protein synthesis
2) Zidovudine, AZT;
Azidothymidine (Retrovir)
O
CH3
HN
N
O
O
HO
N3
3`-Azido-3`-deoxythymidine
• It is active against retroviruses
• It is used orally and metabolised mainly
as glucuronide conjugate
Mechanism of action
Zidovudine, AZT
Thymidylate kinase
monophosphate
Thymidylate kinase
The nucleoside 5' triphosphate
Act as a competitive inhibitor
of the normal nucleoside-5'-triphosphate
for the enzyme (RT)
and/or utilised by RT for
incorporation into incomplete
pro-viral DNA
inhibitition of the reverse transcriptase (RT)
B) Purine nucleoside
analogues
1) Vidarabine (Ara-A)
NH2
N
N
N
HO
N
O
HO
OH
•
•
•
•
9D-Arabinofuranosyladenine
(Adenine arabinoside)
Active against DNA-viruses
An alternative to Trifluridine for treatment of herpes
simplex keratitis
In cases of viral encephalitis, it must be administered by
continuous intravenous infusion .Why?
Converted by viral enzymes to the triphosphate derivative,
which is potent inhibitor of ribonucleotide reductases and
DNA polymerases
2) Acyclovir (Zovirax)
O
N
HN
H2N
N
N
O
CH2OH
2-Amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]
-6H-purine-6-one
(9-[(2-hydroxyethoxy)methyl]-guanine)
• It is an acyclic analogue of 2’-deoxyguanosine
• has potent activity against several DNA viruses
• it is the drug of choice for treatment of genital
herpes.
Mechanism of action
Acyclovir
Viral thymidylate
Acyclovir monophosphate
kinase
Cellular kinases
Acyclovir triphosphate
(has affinity 100 times to viral
DNA polymerase than for human DNA polymerase)
Irreversible binding to
viral DNA polymerase
Inactive enzyme
Incorporated into
the viral DNA
Premature DNA-chain termination
• Due to poor GIT absorption, a bioprecursor of acyclovir
was designed:-
 Desciclovir (lacks the 4-oxo substitution): has
more lipophilic properties that allow better
bioavailability and is converted in vivo by xanthine
oxidase to acyclovir.

Valacyclovir (l-valyl ester): 3-4 times higher
bioavailability than acyclovir. It is converted in vivo
into acyclovir.
3) Ribavirin: (Virazole)
O
N
HOH2C
O
OH
N
C
NH2
N
OH
l-D-Ribofuranosyl-IH-1,2,4-triazole-3-carboxamide
•It is a purine nucleoside analog with a modified
base and D-ribose sugar
•It is considered as antimetabolite that obtained by
molecular dissection of the purine base
•it is a broad spectrum antiviral
•it is used as aerosol in the treatment of influenza A
and B and oral treatment of hepatitis, genital
herpes and measles.
Mechanism of action
Ribavirin
viral and cellular kinases
Ribavirin monophosphates
and cellular phosphorylating enzymes
(RMP)
Ribavirin triphosphates
(RTP)
Inhibits inosine monophosphate
dehydrogenase
Inosine monophosphate
(IMP)
Inhibition of viral RNA
polymerases
Xanthine monophosphate
(XMP)
Guanosine triphosphate synthesis
(GTP)
Thiosemicarbazone
derivatives
Methisazone (Marboran)
N
H
N
NH2
S
O
N
R
Methisazone; R = CH3
(N-Methylisatin--thiosemicarbazone)
Isatine--thiosemicarbazone; R = H
1-EthylIsatine--thiosemicarbazone; R =C2H5
 It interferes with the translation of mRNA messages into
protein synthesis on the cell ribosome producing a defect in
protein incorporation into virus
 Active against poxviruses, including variola and vaccinia
 Also used as a prophylactic agent against smallpox.
Interferons
(IFNs)
 Interferons (IFNs) are potent cytokines that
possess
antiviral,
immunomodulating,
and
antiproliferative actions
 synthesized by cells in response to various
inducers and in turn cause biochemical changes
leading to an antiviral state in cells of the same
species
 Three major classes of human interferons with
significant
antiviral
activity
currently
are
recognized: alpha (>24 individual species), beta,
and gamma(has less antiviral activity but more
potent immunoregulatory effects ).
 Interferon biological activity usually is measured
in terms of antiviral effects in cell culture and
generally is expressed as international units (IU)
relative to reference standards.
Recent Antiviral
Drugs
These agents can be broadly divided into three
major
classes
on
the
basis
of
enzymes
or
processes that they inhibit.
1) Enzymes
transcriptase
inhibitors
(The
(reverse
retroviral
reverse
transcriptase (RT) is an enzyme that is vital for
replication of the AIDS virus. ),
protease or
glucosidase).
2) Viral processes inhibitors. (binding, or
uncoating)
3) The
expression
products inhibitors.
of
genes
or
gene
Enzymes Inhibitors
1HIV Reverse Transcriptase
inhibitors {HIV-RTIs}
A-Nucleoside analogues
{NARTIs}
 AZT, first synthesised as anti-tumour agent,
demonstrated in vitro inhibition of HIV-1 and
subsequently was administered to patients, and
become the first drug to gain FDA approval (1987)
for the treatment of AIDS and AIDS-related
conditions.
O
CH3
HN
HO
O
O
N
N3
Zidovudine (AZT)
 Other purine or pyrimidine nucleoside analogs were
added.
O
• Didanosine (1991),
H3C
• Zalcitabine (1992),
NH
Stavudine
• Stavudine (1994),
(D4T)
• Lamivudine (1995)
N
O
HO
• Abacavir (1998).
O
 They must be converted into their
nucleotide (triphosphate) forms to
exert their antiviral effect
NH2
N
N
HO
O
NH2
N
N
O HO
N
O
O
O HO
N
NH
N
O
S
Zalcitabine (DDC)
Lamivudine (3TC)
Didanosine (DDI)
B-Non-Nucleoside
RT inhibitors
The NNRTIs target the RT enzyme by direct
binding to it. They are Niverapine (1996),
Delavirdine (1997) and Efavirenz (1998)
CH3
N
H
N
O
N
N
Niverapine
2-Protease inhibitors
• The HIV-1 protease is an aspartate proteinase that is
essential for the final step of viral proliferation.
•
It elicits its action at a post-integration stage before
or during viral budding.
• The retroviral protease cleaves the viral precursor
polyprotein gp 160 into proteins that make up the
mature viron; i.e. it hydrolytically attacks the
precursor protein to generate proteins, which are
necessary for the virus.
• The HIV protease inhibitors interfere in this process
and leads to the assembly of nonfunctional virions.
• Saquinavir (1995), Indinavir (1996), Ritonavir
(1996), Nelfinavir (1997) and Amprenavir (1999).
They are frequently used in combination with
Zidovudine and Lamivudine.
H
O
N
N
H
CONH2
H
N
O
Saquinavir
OH
H
N
Ph
O
N
H
3-Glucosidase
inhibitors
 In the processing stage before viral budding,
the viral envelope protein gp 120 is heavily
N-glycosylated, and is followed by a process
of sugar trimming by a group of glucosidase
and mannosidase.
 Enzymes trimming are vital for maturation
and ineffectively of the virus.
 Therefore,
inhibitors
that
inactivate
the
glucosidase enzymes have the potential of
arresting viral replication.
OH
HO
OH
OH
HO
OH
H
OH
N
N
N-Butyldeoxynojirimycin
Castanospermine
OH
O
O
OH
H
N
OH
OH
6-O-Butanoylcastanospermine
Inhibitors of Gene
Expression
Antisense Oligonucleotides
 Antisense technology
discovery method.
is
a
novel
drug
 Antisense drugs work at the genetic level to
interrupt the process by which diseasecausing proteins are produced.
 An oligonucleotide is designed to be
complimentary to a specific nucleotide
sequence in a gene, a gene product, or a
protein of mRNA. Once administrated,
oligonucleotide is expected to seek the
target site, hybridise with it; and thereby
inhibit the normal function of the particular
segment.
 Almost all human diseases are the result of
inadequate or inappropriate production or
disordered performance of proteins
 Traditional drugs are designed to interact
with protein molecules throughout the body
that support or cause diseases.
 Antisense drugs are designed to inhibit the
production of disease-causing proteins
 Antisense molecules designed precisely on
the basis of the genetic code bind specifically
with the messenger RNA and effectively
overcome
its
preventing
genetic
the
signal,
production
thereby
of
disease-associated proteins.
 They can be designed to treat a wide range of
diseases including infectious, inflammatory
and cardiovascular diseases and cancer and
have the potential to be more selective and,
as a result, more effective and less toxic than
traditional drugs.
Chemistry of Oligonucleotides
 Antisense
Oligonucleotides
are
short,
synthetic, single strands of DNA or DNA
analogs called oligodeoxyribonucleotides,
that are complimentary, or antisense to
target sequence (DNA or RNA), which exhibit
sequences - specific binding to RNA targets
within the cell.
 The RNA-DNA complex, which interacts by
classic Watson-Crick base pairing, can
interfere with translation of mRNA in one of
several ways.
 They are designed to stop a biological event
such as transcription, translation or splicing.
HO
O
Oligonucleotide:
X = OPhosphorothioate: X = SMethylphosphonate: X = CH3
Phosphoamidate:
X = NHR or NRR1
B = A, T, C, G
B
O
O
P
O
O
B
X
O
O
P
X
O
O
n
OH
B
Fomivirsen sodium
(Vitravene)
it has been approved in 1998 as an
injectable
related
formula
to
treat
cytomegalovirus
AIDS
(CMV)
retinitis. It is the first drug based on
the antisense technology.
Other antiviral Drugs
Cidofovir (for CMV)
Adefovir (approved 2002 for HBV)
Zanamivir (for Influenza virus)
Foscarnet (for CMV)
Neuraminidase Inhibitors
• Neuraminidase has functions that aid in the
efficiency of virus release from cells.
• Neuraminidase cleaves terminal sialic acid
residues from carbohydrate moieties on the
surfaces of infected cells.
• This promotes the release of progeny viruses
from infected cells.
Neuraminidase Inhibitors
• Neuraminidase also cleaves sialic acid
residues from viral proteins, preventing
aggregation of viruses.
• Administration of chemical inhibitors of
neuraminidase is a treatment that limits the
severity and spread of viral infections.
Neuraminidase Inhibitors
• Act by inhibition of neuraminidase
enzyme.
• Mode of action relies on blocking the
function of viral neuraminidase protein,
thus preventing the virus from budding
from the host cell.
• Oseltamivir, Zanamivir and Peramivir
belong to this class.
Thank you