Antiviral agents

Antiviral Drugs
Prof. K. SURESH KUMAR
KMCH COLLEGE OF PHARMACY
COIMBATORE.

INTRODUCTION
• Viruses can cause a variety of diseases from common cold and
the flu to serious illnesses such as AIDS, dengue fever,
measles, small pox and bird flu.
• All viruses infect cells and hijack the host cellular machinery
for their own benefit.
• Learning about the biology and structure of viruses can help us
better understand the diseases that they cause, their prevention
and treatment.
208/17/18 Antiviral agents

3
VIRAL STRUCTUREVIRAL STRUCTURE

GENERAL CHARACTERISTICS OF VIRUSES
• Viruses may be regarded as exceptionally complex
aggregations of nonliving chemicals or as exceptionally
simple living microbes.
• Viruses contain a single type of nucleic acid (DNA or RNA)
and a protein coat, sometimes enclosed by an envelope
composed of lipids, proteins, and carbohydrates.
• Viruses are obligatory intracellular parasites. They multiply
by using the host cell's synthesizing machinery to cause the
synthesis of specialized elements that can transfer the viral
nucleic acid to other cells.

Host Range
• Host range refers to the spectrum of host cells in which a virus
can multiply. (narrow vs. broad)
• Most viruses infect only specific types of cells in one host
species, so they do not generally cross species barriers.
• Host range is determined by the specific attachment site on
the host cell's surface and the availability of host cellular
factors.

Viral Structure
• A virion is a complete, fully developed viral particle composed of nucleic
acid surrounded by a coat.
• Helical viruses (for example, Ebola virus) resemble long rods and their
capsids are hollow cylinders surrounding the nucleic acid.
• Polyhedral viruses (for example, adenovirus) are many-sided. Usually the
capsid is an icosahedron.
• Enveloped viruses are covered by an envelope and are roughly spherical
but highly pleomorphic (for example, Poxvirus). There are also enveloped
helical viruses (for example, Influenzavirus) and enveloped polyhedral
viruses (for example, Herpesvirus). Pleomorphic: Many-formed. A tumor
may be pleomorphic.
• Complex viruses have complex structures. For example, many
bacteriophages have a polyhedral capsid with a helical tail attached.
Bacteriophage: A virus that infects and lyses certain bacteria.
VIRAL STRUCTUREVIRAL STRUCTURE

Nucleic Acid
• Viruses contain either DNA or RNA, never both, and the
nucleic acid may be single- or double-stranded, linear or
circular, or divided into several separate molecules.
• The proportion of nucleic acid in relation to protein in viruses
ranges from about 1% to about 50%.

DNA viruses
• gene expression is much like that of the host cell
• DNA-dependent RNA polymerase synthesizes mRNA
• Host cell ribosomes and tRNAs used to translate viral
mRNA
• Unique viral proteins include structural proteins and
replication enzymes for viral DNA.
• Example-Herpesvirus, Epstein-Barr (mononucleosis)

RNA VIRUSES
• Cells cannot make copies of RNA. Three kinds of strategies
for RNA viruses:

Positive -strand RNA viruses
• the genome is also a mRNA
• The first task of the virus is to translate viral-specific proteins
including RNA-dependent RNA polymerase (viral
transciption/repliction enzyme) from viral RNA. The enzyme
makes more mRNA and new RNA for viruses.

Positive-stranded RNA: genome is a molecule of
single-stranded "sense" RNA
Examples
• polioviruses
• rhinoviruses (frequent cause of the common "cold")
• coronaviruses (includes the agent of Severe Acute Respiratory
Syndrome (SARS)
• rubella (causes "German" measles)
• yellow fever virus
• West Nile virus
• dengue fever viruses
• equine encephalitis viruses
• hepatitis A ("infectious hepatitis") and hepatitis C viruses
• tobacco mosaic virus (TMV)

NEGATIVE-STRAND RNA VIRUSES
• the genome is the complement of mRNA
• First task of the virus is to make mRNA. Therefore, the virus
imports RNA polymerase or transcriptase as a part of the virus
structure.

Negative-stranded RNA viruses: genome consists of one or more
molecules of single-stranded "antisense" RNA
Examples
• measles
• mumps
• respiratory syncytial virus (RSV), parainfluenza viruses (PIV),
and human metapneumovirus. (In the U.S., these close
relatives account for hundreds of thousands of hospital visits
each year, mostly by children.)
• rabies
• Ebola
• influenza

VIRAL
LIFE
CYCLE
ATTACHMENT
PENETRATION HOST
FUNCTIONS
ASSEMBLY
(MATURATION)
Transcription
REPLICATION
RELEASE
UNCOATING
Translation
MULTIPLICATION

1. Nucleic acid content (DNA/RNA)
2. Viral Morphology (helical, icosahedral etc)
3. Site of replication in celll (cytoplasam/necleus
4. Coating (enveloped/ non enveloped)
5. Serological typing (antigenic)
6. Cell types infected (T, B lymphocyte, monocytes)

RNA VIRUSES
1.Picorano virus (polio)
2.Rhino virus (common cold &pneumonia)
3.Hepatitis A
4.Influenza
5.Rabies virus (rhobdovirus)
6.Retero virus (HIV1 &HIV 2)
7.Human T cell lymphotrophic viruses (HTLV1&2 T cell leukemia & lymphoma
8.Arena virus (meningitis)
9.Orthomyxovirus
10.Paramyxovirus etc
DNA Viruses
1.Herpes virus (HSV&2)
2.Hepatitis B virus
3.Pox virus

Approaches to treat viral diseases
As viruses are intracellular parasites (utilizing host machinery), there
are very few unique targets in viruses
This distinguishes viruses from other infectious organisms:
(Bacteria, protozoa, fungi)
Challenges in designing anti-viral treatments:
Host cell must be immune to treatment! (to limit off-target toxicity)
 Viral infection---symptoms often associated with latency
Period
General anti-viral strategies are to inhibit:
Viral attachment to host cell, penetration, and uncoating
enzymes:
DNA/RNA polymerases, etc
Reverse transcriptases, proteases, etc.

Inhibit viral transcription/ viral translation
Interfere with glycosylation, phosphorylation,
sulphonylation.
Host expression of viral proteins
Assembly of viral proteins
 Release of virus from cell surface membranes

Classification
I.Nucleoside anti metabolites
Inhibitors of DNA polymerase
•Idoxuridine
•Trifluridine
•Vidarabine
•Acyclovir
•Valacyclovir
•Ganciclovir
•Famciclovir
•Cidofovir
•Foscornet sodium

20
Reverse transcriptase inhibitors
•Zidovudine
•Didanosine
•Zalcitabine
•Stavudine
•Lamivudine
Miscellaneous nucleoside antimetabolites
•Ribovirin
II. Drugs used for the treatment of HIV:
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Nevirapine
Delaviridine
Efavirenz
Protease inhibitors
Saquinavir
Indinavir
amprenavir
Ritonavir
Nelfinavir

III. Drugs of a biological origin:
1. Interferons:
Interferon alfa (α)
Interferon alfa-2a
Interferon alfa-2b
Interferon beta (β)
Interferon gamma (γ)
2. Drugs of a herbal origin:
Flacosid
Alpisarin
Helepin
Gossypol

According to their clinical utility antiviral drugs are classified into:
I. Anti-influenza drugs:
a) Adamantane derivatives:
Amantadine
Rimantadine
b) Inhibitors of viral neuraminidase:
Zanamivir
Ozeltamivir
c) Inducers of interferon synthesis:
Arbidol
II. Anti-herpes drugs:
1. Nucleoside analogs:
Acyclovir
Valaciclovir
Famciclovir
Idoxuridine
Ganciclovir

2. Inducers of interferon synthesis:
Cycloferon
III. Drugs used for the treatment of HIV:
1. Inhibitors of reverse transcriptase:
a) Nucleoside reverse transcriptase inhibitors (NRTIs)
Zidovudine (AZT)
Didanozine
Stavudine
Lamivudine
Zalcitabine
b) Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Nevirapine
Efaverenz
2) Protease inhibitors
Saquinavir, Indinavir, amprenavir, ritonavir.

IV. Drugs used for the treatment of cytomegalovirus
infections:
1. Nucleoside analogs:
Ganciclovir
Valganciclovir
Miscellaneous
Foscarnet
V. Antiviral drugs with an extended spectrum of action
(nonselective antiviral drugs):
Ribavirin
Lamivudine
Interferons: Interferon α, etc

Amantadine HCl
•Approved by FDA in 1976 to treat influenza A
•Inhibits the un-coating of the viral genome
•Speifically targets a protein called M2 (an ion channel)
• Inactive against influenza B, which lacks M2
• Pharmacokinetics:
•Well absorbed orally; crosses BBB
•90% excreted unchanged ; no reports of metabolic
products
•Side effects:
•Low toxicity at therapeutic levels; some CNS side effects
(scary
•hallucinations)

08/17/18 Antiviral agents 26
Synthesis

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RIMANTIDINE
alpha-methyltricyclo-[3.3.1.1/3.7]decane-1-methanamine hydrochloride

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9-[2(hydroxyethoxy)methyl]9H guanine
Mechanism:
Acycolvir thymidine kinase acyclovir MonoPO4
guanosine mono Po4 kinase
Acyclovir triPO4
Acyclovir triPO4 compete for deoxy guanine triPO4 and hence it competetively
inhibit DNA polymerase.
It also incorporate with viral DNA chain during DNA synthesis. Because
Acyclovir triPO4 lacks 3’OH group of cyclic sugar, it terminates further
elongation of DNA chain.
ACYCLOVIRACYCLOVIR

29
HN
N N
H
N
O
H2N
+ ClCH2OCH2COOC6H5 HN
N N
N
O
H2N
CH2OCH2COOc6H5
HN
N N
N
O
H2N
O
OH
Guanine Chloromethoxy methyl
Benzoate
Hydrolysis
Reduction

32
IDOXURIDINEIDOXURIDINE

IDOXURIDINE

Its 5 trifluromethyl 2’deoxy uridine
Mechanism
Trifluridine mono PO4 irreversibily inhibits thymidylate synthase
Trifluridine triPO4 cometetively inhibits thymidine triPO4 incorporation into
DNA by DNA polymerase
Tri PO4 form is incorporated into Cellular DNA, crating fragile & poorly
fuctions DNA
USES: keratoconjuctivities & epithelial keratitis due to HSV 1& HSV2
36
TRIFLURIDINETRIFLURIDINE

Its 9[ ( 1,3dihydroxy-2 propoxy) methyl] guanine
It is an analogue of acyclovir with an additional hydroxy
methyl group on acyclic side chain.
MECHANISM
Similar to acyclovir
USES:
Against HSV &VSV and greatly against CMV infection.
37
GANCICLOVIRGANCICLOVIR
HN
N N
N
O
H2N
O
OH
HO

FOSCARNET SODIUM
Tri sodium phosphono formate.
MECHANISM
It does not require any viral or cellular enzymes for Bioactivation
it’s a reversible noncompetitive inhibitor at the pyro PO4 binding site of the viral
DNA polymerase .
They ultimately inhibit cleavage of pyro PO4 from deoxy nucleotide triPO4 and
inhibit incorporation of nucleosidetriPO4 into DNA
USES:
HSV & retero virus

RETROVIRUSES
• Virus has the enzyme reverse transcriptase as a part of the
viral structure.
• A double-stranded DNA copy of the viral genome is produced.
• This copy can integrate into the host cell chromosome.
• Some retroviruses can cause tumors in animals: oncogenes
• Human immunodeficiency virus (HIV) is a retrovirus. This is
the causative agent of AIDS.

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Reverse transcriptase
Viral genomic RNA
cDNA-RNA complex
Double stranded DNA
Which is ready for integration into host chromosome. The enzyme that
catalyze this set of reaction is reverse transcriptase
All classical antireteroviral agents are 2’,3’dideoxy nucleoside analogues.
These agents are acting at earlier stage in the infected cells. Its very weak
Against chronicle stage.

ZIDOVUDINE
Azido thymidine(AZT) 3’ azido 3’ deoxythymidine
Its an analogue of thymidine
Its active against reterovirus HIV-1, HIV-2 and HTLV-1.
Mechanism:
Retero virus possess a RT or a RNA-directed DNA polymerase. It directs DNA copy
Of viral RNA genome which is duplicated, circularized and incorporated in to the
DNA of an infected cell.
AZT thymidine kinase AZT mono PO4 AZT di PO4 AZT tri
PO4. AZT tri PO4 competitively inhibits RT with respect to thymidine tri PO4.
The 3’ azido group prevents formation of 5’,3’ phospho diester bond. So it causes
DNA
Chain termination yielding an incomplete proviral DNA.

AZT mono PO4 competitively inhibits thymidine kinase thus decrease intracellular
thymidine triPO4
Its greater affinity for HIV-RT than humanDNA polymerase.

DIDANOSINE
2’,3’ dideoxy inosine is a synthetic purine nucleoside.
Its bioactivated to 2’,3’ dideoxy inosine tri PO4 by host cell
Enzymes.
Which is competitively inhibit RT & incorporated into viral DNA
Causes chain termination in HIV infected cell.
USES:
Recommended for advanced HIV patient 4408/17/18 Antiviral agents

ZALCITABINE
2’,3’dideoxy cytidine or dideoxy cytidine
Mechanism
Zalcitabine Zalcitabine Mono PO4
Deoxy cytidine Celluar kinase
Mono PO4
Dideoxy cytidine 5’ tri PO4.
Which inhibit RT b competitive inhibition and termination of viral DNA chain.
It also inhibit host mitochondrial DNA synthesis (low concen)------toxicity.
USES: useful against HIV1 & HIV 2.

LAMIVUDINE
(-) 2’,3’ dideoxy 3’ thia cytidine
Its promising antiviral action. It develop resistance as a result of
mutation in codon 184 of the gene that encode HIV-RT
It is combined with AZT and it increase CD4+ counts.
It’s a semisynthetic nucleoside analogue that differ from 2’,3’
dideoxy cytidine by the sustn of a S atom in place of a methylene
group at 3’ position of the ribose ring.

RIBAVIRIN
1 Beta D-ribofuranosyl 1,2,4 triazole 3-carboxamide
It’s a purine nucleoside analogue with modified base and D-sugar moiety
Ribavirin kinase Ribavirin Mono PO4 (RMP) RTP.
RMP inhibits inosine monophosphate dehydrogenase thereby preventing
incorporation of IMP to Xanthine MP. XMP is required for guanosine
triphosphate synthesis.
RTP inhibits viral mRNA polymerase.
Inhibits very wide variety of RNA and DNA viruses. Its used to treat
Respiratory Syncytical Virus (RSV)

SAQUINAVIRSAQUINAVIR
Saquinavir is an oral medication that is used for treating infections with the
h (HIV). It is in a class of drugs called protease inhibitors.
Protease is the enzyme that forms the new structural proteins and enzymes.
Saquinavir blocks the activity of protease and results in the formation of
defective viruses that are unable to infect the body's cells. As a result, the
number of viruses in the body (the viral load) decreases
Saquinavir combine with other reteroviral agent. It lower P24 antigen level
in HIV infected patients & elevate CD4+ counts

RITONOVIRRITONOVIR

INDINAVIRINDINAVIR

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