Antiviral agents history, classification,mechanism of action and adverse effect

1. Antiviral agents
AMIR SOHAIL

2. Virion
• Virus consists of:
• A core genome of Nucleic acid which may be either double stranded
or single stranded DNA or RNA (but not both), surrounded by a
protein shell or capsid.
• Capsid is composed of capsomeres, which consist of one or two
molecules of polypeptides.
• Capsid and its enclosed nucleic acid is called nucleocapsid
• In some viruses a lipoprotein membrane or envelope surrounds the
nucleocapsid and may contain antigenic viral glycoproteins.
• The whole infective particle is called VIRION.
• Viruses are intracellular parasites which utilize host cell machinery
to synthesize new viral protein and genetic material

4. Viruses, who are they?
27 MAR 2007 Antiviral Drugs: An Overview

5. Replication of Viruses
1. Attachment / Adhesion
2. Penetration
i. Endocytosis
ii. Fusion
iii. Translocation
3. Uncoating
4. Transcription (synthesis of mRNA)
5. Translation
i. Early translation (synthesis of proteins)
ii. Late translation (synthesis of proteins)
6. Replication
7. Assembly (formation of capsomeres, capcid,
Nucleocapcid, envelope)
8. Release

10. Classification
• I. Inhibitors of viral attachment and penetration:
Gamma-globulin (IgG):Neutralize viruses and prevent
attachment and penetration
• II. Inhibitors of viral nucleic acid synthesis.
1. Purine analogues
Acyclovir, Valacyclovir, Ganciclovir,
Penciclovir, Ribavirin etc.
2. Pyrimidine analogues
Zidovudine, Idoxuridine, trifluridine, cytarabine etc.
3. Pyrophosphate analogues
Foscarnet
III. Inhibitors of uncoating and viral assembly:
1. Prevent viral uncoating
Amantadine, Rimantadine
2. Neuraminidase inhibitors
Oseltamivir, Zanamivir

11. • IV. Immunomodulators
1. Interferons: Interferon-alpha
2. Interferon inducers: Polyriboinosinic acid
V. Miscellaneous agents
1. Thiosemicarbazones: Methisazone
2. Antibiotics: Rifampicin, Dactenomycin
3. Others: Levamisole, Dextran sulphate

12. Chemotherapy of Viral Infections
• 1. Drugs for respiratory virus infections
• 2. Drugs for Hepatic Viral Infections
• 3. Drugs for Herpes virus infection
• 4. Drugs for HIV Infection

13. Treatment of respiratory virus infections
• A. Neuraminidase Inhibitors: (For type A&B)
• Oseltamivir (Tamiflu)
• Zanamavir (Relenza)
• B. Inhibitors of viral uncoating: (For type A)
• Amantadine
• Rimantadine
C. Ribavirin: (For Respiratory syncytial virus
RSV)
Interference with viral messenger RNA

14. Schematic of Influenza Virus

15. Drugs for Respiratory Virus Infections
• Viral respiratory tract infections for which
treatments exist include those of influenza A
and B and respiratory syncytial virus (RSV).
• A. Neuraminidase inhibitors:
• Neuraminidase is an enzyme found on the virus
which cleaves sialic acid from cell membrane,
leading to a more effective release of viruses.
• Oseltamivir and Zanamivir are effective
against both Type A and Type B influenza
viruses.
• Both drugs are eliminated unchanged in the
urine.

16. Administration and metabolism of oseltamivir and
zanamivir.

17. Drug Examples
Tamiflu-
• Recently sold to 40
countries to battle avian flu
• It is a neuraminidase
inhibitor, it works on both
influenza A and B

18. B. Inhibitors of viral uncoating
• The therapeutic spectrum of amantadine and
rimantadine is limited to influenza A infections,
equally effective in both treatment and prevention.
• Mode of action: The primary antiviral mechanism
of amantadine and rimantadine is to block the
viral membrane matrix protein, M2, which
functions as a channel for hydrogen ion.
This channel is required for the fusion of the viral
membrane with the cell membrane that ultimately
forms the endosome (created when the virus is
internalized by endocytosis).
[Note: The acidic environment of the endosome
is required for viral uncoating.]
• These drugs may also interfere with the release of

19. Administration and metabolism of amantadine and
rimantadine.

20. C. Ribavirin
• Mode of action: The mode of action of ribavirin
has been studied only for the influenza 1. viruses.
The drug is
first converted to the 5'-phosphate derivatives,
the major product being the compound ribavirin-
triphosphate,
which exerts its antiviral action by inhibiting
guanosine triphosphate formation, preventing viral
mRNA capping,
and blocking RNA-dependent RNA polymerase.
• [Note: Rhinoviruses and enteroviruses, which
contain preformed mRNA and do not need to
synthesize mRNA in the host cell to initiate an
infection, are relatively resistant to the action of
ribavirin.]
• It is used for RSV in infants and children, but not

21. Administration and metabolism of ribavirin.

22. Drugs for Hepatic Viral Infections
• A. Interferon ( for HBV & HCV)
• B. Lamivudine ( for HBV & HIV)
• C. Adefovir (hepatitis B and herpes
simplex virus infection).
• D. Entecavir ( for HBV)

23. Drugs for Herpesvirus infection
• A. Acyclovir
• B. Cidofovir
• C. Fomivirsen
• D. Foscarnet
• E. Ganciclovir
• F. Penciclovir and famcicolvir
G. Vidarabine
H. Trifluridine

24. Drug Examples

27. Administration and metabolism of acyclovir

28. Administration and metabolism of ganciclovir.

29. Administration and metabolism of penciclovir and
famciclovir.

30. Summary of selected antiviral agents.

31. Treatment for HIV Infection
• Approval of zidovudine in 1987.
• Multi drug regimen is commonly referred to as highly
active antiretroviral therapy,or HAART.
• There are five classes of antiretroviral drugs, each of
which targets one of four viral processes.
• These classes of drugs are:
I. Nucleoside and nucleotide reverse transcriptase
inhibitors (NRTIs)
2. Non-nucleoside reverse transcriptase inhibitors
(NNRTIs),
3. Protease inhibitors,
4. Entry inhibitors .
5. Integrase inhibitors.
• The current recommendation for primary therapy is to
administer two NRTIs with either a protease inhibitor
or an NNRTI.

32. • To enable HIV to be integrated into the
host DNA and so use the cell's genetic
machinery to make new virus, the single-
stranded viral RNA must first be converted
to double-stranded DNA by the viral
enzyme reverse transcriptase, while the
enzyme RNAse-H hydrolyses the RNA
after it has been copied. Nucleoside and
non-nucleoside reverse-transcriptase
inhibitors are two classes of antiretroviral
drugs that suppress HIV replication by

35. • A. Nucleoside reverse-transcriptase
inhibitors are similar in structure to the
building blocks that make up DNA. By
incorporating themselves into the DNA
nucleoside chain being produced by
reverse transcriptase, they stop
attachment of further nucleosides and so
prevent ongoing viral DNA synthesis.
• B. Non-nucleoside reverse transcriptase
inhibitors attach to the reverse
transcriptase and affect the activity of the
enzyme by restricting its mobility and

36. Mechanism of action of nucleoside and non-nucleoside reverse-
transcriptase inhibitors

37. Highly active antiretroviral therapy (HAART).

38. 1.NRTIs For HIV
• Zidovudine (AZT)
• Stavudine (d4T)
• Didanosine (ddI)
• Tenofovir (TDF)
• Lamivudine (3TC)
• Emtricitabine (FTC)
• Zalcitabine (ddC)
• Abacavir (ABC)

41. • Nucleoside analog reverse transcriptase
inhibitors (NRTIs) are nucleoside
analogues that act as competitive
inhibitors of HIV-1 reverse transcriptase.
These drugs compete with nucleoside
triphosphates for access to reverse
transcriptase.
• All NRTIs lack a 3-hydroxyl group; thus,
their incorporation into a growing DNA
chain results in its termination. They
require intracytoplasmic activation via
phosphorylation by cellular enzymes to the

42. • List of NRTIs
• Zidovudine or azidothymidine (AZT) (also
called ZDV): first approved drug in its class.
• Didanosine (ddI): second FDA-approved drug
for the treatment of HIV infection.
• Tenofovir (TDF): first nucleotide analog. It has
significant drug interactions.
• Lamivudine (3TC): also used in the treatment
of HBV infection.
• Emtricitabine (FTC): acts as an inhibitor of
HBV and HIV transcriptase.
• Abacavir (ABC): a guanosine analog

43. Administration, metabolism, and toxicity of zidovudine
(AZT).

44. 2. NNRTIs Used to Treat AIDS
• A. Nevirapine (NVP)
• B. Delavirdine (DLV)
• C. Efavirenz (EFV)

45. Administration, metabolism, and toxicity of nevirapine.

46. Administration and metabolism of efavirenz.

47. Protease inhibitors
• After transcription in the nucleus, viral mRNA
enters the cytoplasm and uses the host's
cellular machinery to manufacture virus
proteins. The viral components then gather at
the cell membrane and immature viruses bud
off the cell. Core proteins are produced as
part of long polypeptides, which must be cut
into smaller fragments by the enzyme
protease in order to form mature, functional
proteins.
• Protease inhibitors bind to the site where
protein cutting occurs, and so prevent the
enzyme from releasing the individual core

48. Mechanism of action of protease inhibitors

49. HIV Protease Inhibitors
• Ritonavir (RTV)
• Saquinavir (SQV)
• Indinavir (IDV)
• Nelfinavir (NFV)
• Fosamprenavir (fAPV)
• Lopinavir (LPVr)
• Atazanavir (ATV)
• Tipranavir (TPV)
• Darunavir (DRV)

50. Integrase Inhibitors
Raltegravir (RAL)
Integrase is one of three HIV-1 enzymes
required for viral replication
Results in integration of HIV-1 DNA into host cell
genome
Raltegravir targets viral integrase

51. Antiretroviral : Novel Agents in Clinical
Development
51
Fusion inhibitors
Reverse
transcriptase
inhibitors
Mature
virus
Protease
inhibitors
Integrase
inhibitors
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