A comprehensive yet concise approach to understanding the fundamentals of Antiviral drugs from pharmacological point of view. Made for quick review before shelf exams, professional exams and board exams.

1. Antiviral Drugs
Dr. Hammad Ali

2. Outline
- Viruses, their structure, types
- Replication cycle
- Drug strategies (Herpes, Influenza, AIDS, Hepatitis C)
- Interferons & newer drugs

3. Viruses
- Infective particles
- Requires a host to thrive, replicate
- Structure:
DNA viruses
RNA viruses
A genetic particle
A capsid (protein covering)

5. Replication Cycle
(of majority viruses)

6. Antiviral Drugs
(except HIV)

7. HIV structure

8. Replication Cycle
(HIV)

9. Antiretrovirals
(HIV)

10. Antivirals
- Many are antimetabolites (purine, pyrimidine bases)
- Requires bioactivation by kinases

11. ‘-ovir’ Herpes (omggg!!!)
‘-avir’ AIDS
‘-ivir’ Influenza
‘-uvir’ or ‘-evir’ Hepatitis C

12. Influenza
Neuraminidase inhibitors:
Oseltamivir
Zanamivir
Mechanism: Inhibits influenza enzyme NA
- Causes newly syn. Virus to adhere cell surface
- Prevents viral penetration of mucus secretions
Dissolves mucus &
cleaves Sialic Acid
residues to release
viral progeny
Treatment
Prevention
Both influenza A, B - Begin therapy within 48hours of illness

13. Antimetabolites

15. Mechanism:
Host cell
Kinase
Nucleotide:
Cidofovir
Tenofovir
Nucleoside (HIV):
Zidovudine
Lamivudine
Viral Kinase
Nucleosides:
Acyclovir
Valacyclovir
Ganciclovir
Activated
Nucleotide
Analogue
Inhibits viral
DNA/RNA
Polymerase
- Chain
termination
NNRTIs
Foscarnet
No myelosuppression
*All drugs that involve host cell kinase generally cause B.M suppression except Acyclovirs

16. Anti-Herpes Virus

17. Acyclovir
- MOA: Guanosine analogues
Activated via mono-phosphorylation (1st)
by viral Thymidine Kinase TK
- Resistance = TK absent
- Uses:
HSV, VZV & shingles
(both prophylaxis & treatment)
S/E: Crystalline Nephropathy, obstructive
(Acute renal failure)
Neurotoxicity
Hydration

18. Valacyclovir
Famciclovir

19. Ganciclovir
- MOA: Activated via mono-phosphorylation (1st)
by viral Thymidine Kinase of CMV and
HSV
- Is more toxic to host cell enzymes
- Uses:
CMV, HSV, VZV
S/E: B.M Suppression – ‘penias’
Crystalline Nephropathy, obstructive
(Acute renal failure), Neurotoxicity

20. Cidofovir
- MOA: Inhibitor of DNA Polymerase
Doesn’t require phosphorylation!
S/E: Nephrotoxicity
Foscarnet
- MOA: Direct inhibitor of DNA/RNA Polymerase/ RT
Binds to pyrofosphate-binding site of enzyme
Doesn’t require act. by Kinase
(phosphorylation)
S/E: Nephrotoxicity
Electrolyte imbalance (Ca, PO4, Mg, K)

21. - Clinical Uses:
CMV retinitis, acyclovir-resistant HSV

22. Anti-Retroviral Drugs
(HIV)

23. Replication Cycle
(HIV)

24. 1- Reverse Transcriptase -
- Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
- Non- nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
2- Protease Inhibitors
3- Integrase Inhibitors
4- Fusion Inhibitors

25. - MOA: Inhibit nucleotide binding to Reverse
Transcriptase. Causes DNA termination
- All need to be phosphorylated
- Resistance? RT gene mutation
Tenofovir = NtRTI
NRTIs
- Nucleoside Reverse Transcriptase Inhibitors
Zidovudine (AZT)
Didanosine
Lamivudine
Emtricitabine
Stavudine
Abacavir

26. Side Effects: Lactic Acidosis
Lipodystrophy
Hypersensitivity
Pancreatitis
Bone Marrow suppression
Abacavir
NRTIs
Didanosine
Zidovudine

27. - MOA: Binds Reverse Transcriptase at site
different than NRTIs. Causes DNA termination
Do not require phosphorylation
No myelosuppression!
NNRTIs
- Non-nucleoside Reverse Transcriptase Inhibitors
Delavirdine
Efavirenz
Nevirapine

28. Side Effects: Rash including Steven Johnson
Hepatotoxicity
Neuropsychiatric
C/I in Pregnancy
NNRTIs
Delavirdine
Efavirenz

29. - MOA: Prevents polypeptide (mRNA product)
cleavage into functional parts.
Prevents maturation of new virus
Ritonavir-boosted PI
Protease Inhibitors
- Ritonavir can ‘boost’ drug concentration of other PIs
CYP-450 inhibitor
Ritonavir
Saquinavir
Lopinavir
Indinavir
Darunavir

30. Side Effects: Nephrolithiasis
Diabetes
Central adiposity
GI disturbance (Nausea, diarrhea )
Protease Inhibitors
Insulin resistance

31. - MOA: Inhibit HIV integrase
Prevents viral genome integration into the
host chromosome
Integrase Inhibitors
Raltegravir
Dolutegravir
Side Effects: Myopathy (Elevated Creatine Kinase)

32. - Maraviroc: Binds CCR5 on macrophages/T cells
and prevents interaction with gp120
on the virus surface
- Prevents docking
- Enfuvirtide: Inhibit viral entry by binding to gp41
Prevents fusion
Fusion Inhibitors

33. HIV structure

34. HAART
- Highly active antiretroviral therapy;
2 NRTIs + A Protease or Integrase Inhibitor
• Often initiated at the time of diagnosis
• Decrease chances of resistance
• Especially beneficial in patients with:
AIDS-defining illness
or Low CD+4 cell count (<500cells/mm3)
or High Viral Load

35. HIV Post-exposure prophylaxis:
e.g. Needle-stick injury
Emtricitabine + Tenofovir + Raltegravir

36. +
Pregnancy with HIV:
e.g. To prevent transplacental transfer
(Emtricitabine or Lamivudine) (Zidovudine or Tenofovir)
Ritonavir + (Atazanavir or Lopinavir)
2 NRTIs
+
A Ritonavir-boosted PI

37. Hepatitis C

38. Hepatitis C therapy
- Ribavirin
- Sofosbuvir *
- Simeprevir
- Lepidasvir
- Interferon α
Newer drugs

39. Ribavirin
- Mono-Phosphorylated form
- Triple-Phosphorylated form
IMP dehydrogenase -
RNA Polymerase -
5’ cap of mRNA -
Uses: Chronic Hepatitis C , RSV
Side Effects: Hemolytic anemia
Teratogenic

40. Sofosbuvir
- Inhibits HCV RNA-dependent RNA Polymerase (NS5B)
& acts as a chain terminator
- Dasabuvir
Combination: ribavirin, semiprevir, lepidasvir and/or IFN α
Uses: Chronic Hepatitis C
Do not use as monotherapy
Non-structural protein 5 B

41. Simeprevir
- HCV Protease Inhibitor (NS3/4A)
Prevents viral replication
Uses: Chronic Hepatitis C
Do not use as monotherapy
Lepidasvir
- HCV viral phosphoprotein inhibitor (NS5A); which plays a
role in replication

42. HCV Life Cycle

43. Interferons
- Glycoproteins synthesized normally by virus-infected cells
- Acts on infected & non-infected neighbor cells
i.e. autocrine, paracrine signalling
Causes them to shut down cell’s protein synthesis
• RNA Endonuclease/RNase L activation
• Protein Kinase activation

44. Interferon α
• Ribonuclease L (Rnase L) activation
• Protein Kinase R activation
Digests viral RNA
Inhibits eIF-2 that prevents
viral protein synthesis
Uses: Chronic Hepatitis B & C
Kaposi sarcoma, HPV
Hairy cell leukemia
Malignant melanoma
Renal Cell CA

45. PEG-Interferon α
Polyethylene glycol (PEG) – Pegylated is more effective
- longer half-life
- administered once a week rather than 3/week
- sustained peaks after SC injection
- Twice as effective as IFN

46. Interferon β Multiple sclerosis
Interferon Ɣ Chronic granulomatous disease
Side Effects: Flu-like illness
Depression
Neutropenia
Myopathy

47. Antiviral Drugs
(except HIV)

48. Antiretrovirals
(HIV)

49. Questions?