Viruses are sub-microscopic obligatory intracellular

parasites consisting either of DNA or RNA and a

protein coat.

They lack both the cell wall and the cell membrane

and do not carry out 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

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 are substances used in

the treatment and 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.

Amantadine

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

NH2 .HCl

1-Adamantanamine hydrochloride

• Adamantane derivatives are uniquely configured tricyclic amines.

• They are useful for prevention but not treatment of influenza caused by influenza A virus.

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

1) Trifluridine (Viroptic)

• 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 kerato-conjunctivitis caused by herpes simplex (HSV).

HN

N

O

CF3

O

O

HO

HO

-Trifluorothymidine;2`-Deoxy-5-(trifluoromethyl)-uridine

Mechanism of action

TrifluridineViral thymidylate

kinaseMonophosphate

Cellular kinases

Triphosphate(an inhibitor and a substrate of

viral DNA polymerase)

Inhibition of viral DNA synthesisand producing false DNA

Strand breakage

miscode errors in RNAand protein synthesis

2) Zidovudine, AZT; Azidothymidine (Retrovir)

• It is active against retroviruses

• It is used orally and metabolised mainly as glucuronide conjugate

HN

N

O

CH3

O

O

N3

HO

3`-Azido-3`-deoxythymidine

Mechanism of action

Zidovudine, AZTThymidylate kinase

monophosphate

The nucleoside 5' triphosphate

Thymidylate kinase

inhibitition of the reverse transcriptase (RT)

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

1) Vidarabine (Ara‑A)

• 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

N

N N

N

NH2

O

OH

HO

HO

9 D-Arabinofuranosyladenine(Adenine arabinoside)

2) Acyclovir (Zovirax)

• 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.

HN

N N

N

O

O

CH2OH

H2N

2-Amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purine-6-one

(9-[(2-hydroxyethoxy)methyl]-guanine)

Mechanism of action

AcyclovirViral thymidylate

kinase

Acyclovir triphosphate(has affinity 100 times to viral

DNA polymerase than for human DNA polymerase)

Acyclovir monophosphate

Cellular kinases

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)

•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.

N N

N

O

OHOH

HOH2C

C

O

NH2

l-D-Ribofuranosyl-IH-1,2,4-triazole-3-carboxamide

Mechanism of actionRibavirin

viral and cellular kinases

and cellular phosphorylating enzymesRibavirin monophosphates

(RMP)

Ribavirin triphosphates (RTP)

Inhibition of viral RNA polymerases

Inhibits inosine monophosphate dehydrogenase

Inosine monophosphate (IMP)

Xanthine monophosphate (XMP)

Guanosine triphosphate synthesis (GTP)

Methisazone (Marboran)

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.

N

R

O

N

HN NH2

S

Methisazone; R = CH3(N-Methylisatin--thiosemicarbazone)Isatine--thiosemicarbazone; R = H1-EthylIsatine--thiosemicarbazone; R =C2H5

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.

These agents can be broadly divided into three

major classes on the basis of enzymes or processes

that they inhibit.

1) Enzymes inhibitors (reverse transcriptase

(The 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 of genes or gene products

inhibitors.

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.

HN

N

O

O

N3

CH3

O

Zidovudine (AZT)

HO

Other purine or pyrimidine nucleoside analogs were added.• Didanosine (1991),• Zalcitabine (1992), • Stavudine (1994), • Lamivudine (1995)• Abacavir (1998).

They must be converted into their nucleotide (triphosphate) forms to exert their antiviral effect

N

NH

O

O

O

H3C

Stavudine (D4T)

HO

N

N

O

Zalcitabine (DDC)

NH2

OHO N

N

O

S

NH2

O

Lamivudine (3TC)

HOO

N

NHN

N

O

Didanosine (DDI)

HO

The NNRTIs target the RT enzyme by direct binding to it. They are Niverapine (1996), Delavirdine (1997) and Efavirenz (1998)

N

HN

NN

OCH3

Niverapine

• 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.

NNH

HN N

O CONH2 OH

OPh O N

H

H

H

Saquinavir

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.

N

OHHO

OH

OH

N-Butyldeoxynojirimycin

N

OH

OH

OHHO

H

Castanospermine

N

OH

OH

OHO

HO

6-O-Butanoylcastanospermine

Antisense technology is a novel drug discovery method.

Antisense drugs work at the genetic level to interrupt the process by which disease-causing 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

genetic signal, thereby preventing the production

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.

OHO

O

P OO

X

B

O

O

P OO

X

B

O

OH

B

n

Oligonucleotide: X = O-

Phosphorothioate: X = S-

Methylphosphonate: X = CH3

Phosphoamidate: X = NHR or NRR1

B = A, T, C, G

Fomivirsen sodium (Vitravene)

it has been approved in 1998 as an

injectable formula to treat AIDS related

cytomegalovirus (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.