1. Antiviral drugs

2. Different living organisms

3. Antiviral Drugs
Viruses are infectious agents that need host cell in order to survive and multiply.
Their structure are simple and designed to protect them from environment and to facilitate their entry into cells.
They have Many different shapes

4. 1- Capsid : protein coat surrounding nucleic acid (core)
Structure of the virus
It consists of :
1- Capsid : protein coat surrounding nucleic acid (core)
2- Core consist of nucleic acid which is either DNA or RNA . The combination of capsid and core is called nucleocapsid
3- Lipid membrane may be present.
the complete viral particle is called viron
Lipid membrane
Capsid

5. Life cycle of viruses

6. Replicative cycles of herpes simplex virus, an example of a DNA virus, and the probable sites of action of antiviral agents.

7. Replicative cycles of influenza, an example of an RNA virus, and the sites for effects of antiviral agents.

8. DNA viruses RNA viruses Replicate in nucleus
Classification of the Viruses
DNA viruses
RNA viruses
DNA
Replicate in nucleus
Host RNA- dependant DNA polymerase enzyme
DNA → m-RNA → protein synthesis
RNA
Replicate in cytoplasm
Using viron Reverse Transcriptase enzyme
RNA → ss DNA → ds DNA→ m-RNA → protein synthesis
Antiviral Drugs
A- Antiviral against DNA virus
- change sugar
- change base
B- Antiviral against RNA virus
- Against flu virus
- Against HIV virus
- Against Hepatitis C virus

10. 1- Antiviral drugs used against DNA viruses
Inhibitors of DNA polymerase
A) Changes in Sugar
Acyclovir
zovirax®
MOA
Acyclovir is phosphorylated by viral thymidine kinase → monophosphate → then by cellular thymidine kinase → triphosphate (active form)
The active forms:
- Incorporated in viral DNA chain terminate chain elongation (no 3’OH)
- competitively inhibits viral DNA polymerase leading to arrest of viral
DNA replication
Selectivity of acyclovir to viral thymidine kinase is 200 times that of mamalian enzyme therefore in normal uninfected cells it remains as prodrug
USES: Herpes Simplex

12. MOA B) Changes in heterocyclic ring
In contrast to Acyclovir these drugs are phosphorylated equally by viral and cellular thymidine kinase → less selective → more toxic side effects
First they are activated by phosphorylation with host cell thymidine kinase to the triphosphate active form →
1- inhibit viral DNA polymerase
2- are incorporated in viral DNA → altered DNA , faulty protein synthesis :

13. Iodoxuridine Ribavarin Virazole® 1)Antimetabolite for thymidine
2) Antimetabolite forguanosine
Uses:
Topical treatment of herpes
acts against DNA and RNA viruses
Uses :
Broad spectrum : influenza A & B
Hepatitis C
Iodoxuridine
Ribavarin
Virazole®

14. Ribavirin mechanism of action
Ribavirin is a guanine analog that is phosphorylated by adenosine kinase to its most active form, ribavirin-triphosphate. This compound inhibits viral RNA-polymerase preferentially at therapeutic doses by competing with adenosine-triphosphate and guanine-triphosphate for binding sites at the polymerase, as well as inhibiting transferases necessary for the addition of guanine.

15. 4) Antimetabolite for Cytosine:
3) Antimetabolite for Adenosine:
Fludarabine
Fludara®
cancer ther.
Isolated Streptomyces antibioticus
First studied as anticancer drug
Interfere with DNA synth
Rapid metab. adenosine deaminase
4) Antimetabolite for Cytosine:
Cytarabine (ARA-C)
Cytarabin®, Cytosar®,

17. 2- Antiviral drugs used against RNA viruses,
a) flu viruses
Structure of influenza virus
1- Nucleocapsid contains RNA
2- Nucleocapsid is surrounded by envelope formed of 2
glycoproteins:
Neuraminidase :degrades mucous layer in host respiratory
tract enhancing penetration of virus
Haemaglutinin : binds viron to RBCs causing
haemaglutination ( acidic condition)

18. 2- Antiviral drugs used against RNA viruses,
A) Flu viruses
a) Ion channel disruptors
Rimantadin
Amantadin
Adamin®
MOA
Inhibit penetration of virus to host cell and uncoating of viral nucleic acid
A- at low concentration ; it inhibits replication of virus by blocking a viral ion channel protein
B- at high concentration it prevents the acidic environment needed for haemaglutinin
S.E CNS : nervousness, headache, drowsiness, rimantadine has fewer side
Effects due to its extensive biotransformation
USES prevention and treatment of influenza A virus especially A2 strain(asian influenza which is fatal) and have no effects on influenza B

19. Oseltamivir Tamiflu® Inhibits viral neuraminidase enzyme
b) Neuraminidase inhibitors
Oseltamivir
Tamiflu®
(“Take my flu”)
Zanamivir
Relenza®
Oseltamivir
Tamiflu®
MOA
Inhibits viral neuraminidase enzyme
it may be given as preventive measure either during a community outbreak
or following close contact with an infected individual -
USES: influenza A ( avian flu) and influenza B

20. Binding of oseltamivir to NA
Hydrophobic pocket
Ester moiety is essential
For oral activity as it`s
A prodrug
Basic centre better binding than DANA

21. 2- Antiviral drugs used against RNA viruses,
B) HIV viruses
a) Nucleoside Reverse transcriptase inhibitors
Zidovudine
Azidothymidine AZT
MOA
Antimetabolite for thymidine
Phosphorylation of 5’-OH by cellular thymidine
kinase → tri-PO4 form → competitive inhibition of reverse
transcriptase needed in viral replication
The 3’- azido group prevents formation of 5’3’- phosphodiester bond
causing DNA chain termination
USES
AIDS

22. b) Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)
Binds directly to RT
Nevirapin
Viramune®
Efavirenz / Sustiva
Stocrin®
FDA 1998
Already resistance
J Med Chem 2004, 5923
activity resist strains
Wild type RT
mutated

23. c) Protease Inhibitors
The HIV-1 protease is an enzyme crucial
for the maturation and assembly of infectious viral particles

24. Saquinavir Fortovase® Ritonavir Norvir®
-FDA March 1996, now many resistant strains
-Ritonavir inhib. 3A4 isozyme of CypP450
Used in combi. with other protease inhib.
to suppress their metab.
Indinavir
Crixivan®
Nelfinavir
Viracept®

25. 2- Antiviral drugs used against RNA viruses,
C) Hepatitis C viruse
a) Viral penetration inhibition
Interferon
Intron®
Are small natural proteins released by infected cells in response to foreign invaders to protect uninfected cells
It is an early defense mechanism before antibody formation
MOA
1- inhibition of viral penetration
2- inhibition of transcription and translation of virus
3- activate the formation of cellular inhibitory proteins
to terminates the production of viral nucleic acid
4- inhibition of viral assembly
USES: recombinant DNA methods are used to generate interferon
1-Chronic hepatitis C and B

26. 2- Antiviral drugs used against RNA viruses,
C) Hepatitis C viruse
b) RNA Polymerase inhibitor
Sofosbuvir (brand names Sovaldi,Hepcinat, Resof) is a nucleotide analog used in combination with other drugs for the treatment of hepatitis C virus (HCV) infection. It has been marketed since 2013.
Mode of action:
It inhibits the RNA polymerase that the hepatitis C virus uses to replicate its RNA.
Use:
Sofosbuvir is used for the treatment of chronic hepatitis C, genotypes 1, 2, 3, and 4, in combination with interferon and ribavirin, or with ribavirin alone.
Side effects :
Fatigue, headache, nausea, rash, and irritability