Anti-viral agents

MARIA SHUAIB

46-E

SEMESTER 10

What are viruses?

VIRUSES:

Single or double stranded DNA or RNA enclosed in a protein –

CAPSID

Obligate intracellular parasite

Replication depends on synthetic processes of the host cell

Antiviral drugs must either block entry or exit from cell or be active

inside the host cell

Viral replication:

Adsorption and penetration into susceptible host cells

Un coating of viral nucleic acid

Synthesis of early regulatory proteins

Synthesis of RNA or DNA

Synthesis of late regulatory proteins

Assembly (maturation) of viral particles

Release from cells

Acyclovir

A widely used antiviral with main implications in the treatment of herpes

Seen as a “new age” in antiviral therapy, Gertrude Elion, its creator, was given the Nobel prize for medicine in 1988

It is a nucleoside analogue and prevents viral replication in infected cells

Extremely selective and low in toxicity

Structure of acyclovir:

ACYCLOVIR

Acyclovir

ACV is synthetic analogue of deoxyguanosine , in which the

carbohydrate moiety is acyclic

PROPERTIES:

Acyclovir occurs as chemically stable, white crystalline

solid.

Its slightly soluble in water.

Because of its amphoteric nature, its solubility is increased

with both strong acids and bases.

Mechanism of action:

There are three mechanisms by which ACV show antiviral activity:

1) 1st mechanism

1 2 3

ACV ACV-monophosphate ACV- diphosphate ACV-triphosphate

1: viral thymidine kinase2: normal cellular enzyme,

2: guanosine monophosphate kinase

3: normal cellular enzyme ,guanosine monophosphate kinase

ACV- triphosphate competitively inhibits the viral DNA polymerase

Mechanisms:

2nd mechanism: viral DNA polymerase is competitively inhibited by

ACV-TP with lower median inhibition concentration (IC50) compared

to cellular DNA polymerase.

ACV-TP is incorporated into viral DNA chain during DNA synthesis

because ACV-TP lacks 3`-hydroxyl group of cyclic sugar, it terminates

further elongation of DNA chain.

3rd mechanism: as preferential uptake of ACV by herpes infected cells as compared to uninfected/normal cells resulting in higher

concentration of ACV-TP and leading to high therapeutic index.

Uses:

Effective against the following:

1. Herpes simplex virus type I (HSV-1)

2. Herpes simplex virus type II (HSV-2)

3. Varicella zoster virus (VZV)

4. Epstein-Barr virus (EBV)

5. Cytomegalovirus (CMV) -- least activity

Uses:

ACV is active against most species in herpes virus family.

Decreasing order of activity includes:

HSV-1 > HSV-2 > VZV > EBV > CMV

Some advantages:

Human cells unaffected by viral infection remain unaffected by drug.

Affinity of ACV for viral thymidine kinase is 200 times more then

corresponding mammalian enzyme

Resistance to ACV is only due to mutation in viral thymidine kinase and

less often by mutations in viral DNA polymerase

Valacyclovir:

Valacyclovir is an amino acid ester pro drug of ACV that exibits antiviral activity only

after metabolism to ACV in intestinal walls and liver and then convert to ACV-TP later.

Structurally it differs from ACV by the presence of valine amino acid at 5`hydroxyl group

of nucleoside.

VALACYCLOVIR ACV ACV-MP ACV- DP ACV-TP

BENEFITS OF VALACYCLOVIR:

Show increase GI absorption resulting in higher plasma concentration of drug

Its active against HSV-1,VZV,CMV

Oral valacyclovir is used for treatment of acute localized herpes zoster(shingles)

Structure of Valacyclovir:

Ribavirin:

Ribavirin have broad spectrum activity, it is purine nucleoside analogue with modified base and D-ribose sugar moiety

PROPERTIES:

It is white, crystalline and polymorphic solid

Its soluble in water and chemically stable

Chemical structure of Ribavirin

Mechanism of action:

Ribavirin nucleoside is bioactivated by viral and host cellular kinase to produce

Ribavirin Monophosphate (RMP) and Ribavirin Triphosphate (RTP)

RMP: inhibit conversion of inosine monophosphate (IMP) to Xanthine Monophosphate

(XMP)

XMP: is required for guanosine triphosphate (GTP) synthesis

RTP: inhibits viral RNA polymerases, it also prevent the end capping of viral mRNA by

inhibiting guanyl-N`-methyl tranferase

Emergence of viral resistance to ribavirin has not been documented.

Uses:

Ribavirin inhibit replication of wide variety of RNA and DNA viruses including:

Orthomyxoviruses poxviruses

Paramyxoviruses bunyaviruses

Arenaviruses adenoviruses

Herpes viruses rhinoviruses

Vacinnia influenza (type A and B)

Despite of broad spectrum activity Ribavirin has been approved only for one indication of treatment of severe lower respiratory infection by RSV in carefully

hospitalized infants and children.

Tromantadine HCL

Tromantadine is an anti-viral agent which is active against herpes

simplex virus.

It is available in a topical gel under the trade name Viru-Merz

Its performance is similar to acyclovir

Like rimantadine and amantadine, it is an derivative of adamantine

Mechanism of action

Tromantadine inhibits early and late events in the viral replication

cycle

It inhibits penetration of viruses as well as un coating of virions

It changes the glycoproteins of host cells, therefore impeding the

absorption of virus

Chemical structure of Tromantadine HCL

THANK YOU