1. ANTIVIRALS, INTERFERON AND VACCINES
EDWARD-BENGIE L. MAGSOMBOL, MD, FPCP, FPCC, DASNC
Associate Professor in Microbiology

2. Antivirals APPROACH TO ANTIVIRAL CHEMOTHERAPY
1. Adsorption, Penetration and Uncoating
= little is known about the specific reactions involved
= only amantadine, rimantadine used vs influenza A
= HIV, rhino, EBV now being researched on
2. Replication of Viral Nucleic Acids
= attack enzymes which catalyze replication
= not present in uninfected cells
= all RNA viruses, pox, herpes and
adenovirus

3. Antivirals APPROACH TO ANTIVIRAL CHEMOTHERAPY
3. Integration of Viral Genomes into Cellular Genomes
= as part of multiplication cycle (retrovirus and its integrase)
= tumorigenesis (papovavirus, herpes)
4. Synthesis of Viral Messenger RNA’s
= virus-encoded RNA polymerases, capping enzymes

4. Antivirals APPROACH TO ANTIVIRAL CHEMOTHERAPY
5. Synthesis of Viral Proteins
= viral mRNA translation different from host mRNA
6. Viral Morphogenesis
= enzymes which cleave precursors for viral capsid CHONs
= ex. viral proteases

5. Antivirals CLASSES OF ANTIVIRAL AGENTS Synthetic Antiviral Agents
I. Analogues of Ribonucleosides and Deoxyribonucleosides
= nucleic acids base or derivatives
= included into nucleic acid, usually DNA
= interfere with nucleic acid function
= selectively inhibit viral polymerases
A. Idoxuridine and Trifluorothymidine
= analogues of thymidine, inhibits viral DNA formation
= inhibit multiplication of herpesviruses
= used for topical treatment of herpes simplex keratitis
= not used for systemic use because of toxicity

6. Herpes keratoconjunctivitis

7. Herpes simplex

8. Herpes simplex

9. Herpes simplex

10. Antivirals B. Vidarabine (Adenosine arabinoside, Ara-A)
= inhibits HSV and VZV multiplication
= act as chain terminators; inhibit viral DNA polymerase more than host DNA polymerase
= herpes simplex keratitis; herpes simplex encephalitis (IV route)
C. Acyclovir
= guanine linked to an open ring analogue of ribose, deoxyribose
= thymine or cytosine derivative
= phosphorylated by HSV and VZV TKinases
= topical or IV in mucocutaneous herpes simplex in immunocompromised hosts and also in genital
herpes simplex infections

11. CHICKENPOX (VARICELLA)

12. Antivirals D. Ganciclovir
= close relative of acyclovir; inhibits HSV multiplication
= better substrate for HSV TK than acyclovir
= best inhibitor of CMV multiplication in use
= probably not a strict chain terminator unlike acyclovir
E. Zidovudine (Azidothymidine, AZT, Retrovir)
= inhibits retrovirus reverse transcriptase
= chain terminator because it does not possess a 3’-OH group
= demonstrated clinical efficacy in HIV

13. CYTOMEGALOVIRUS

14. AIDS

15. Antivirals F. Ribavirin (Virazole)
= analogue of purine precursor of 5-aminoimidazole 4-carboxamide
= wide spectrum: good vs RNA and DNA viruses
= target: virus-encoded nucleic acid polymerases
= affects elongation and initiation (less extent)
= for severe RSV infection (aerosol) in children
= reduce mortality on patients with Lassa fever

16. RSV infection (bronchiolitis)

17. RESPIRATORY SYNCYTIAL VIRUS

18. Antivirals
Others
= analogues of thymidine (BVdU) and cytosine (FIAC) - good vs herpesvirus DNA polymerases with low toxicity
= 2’, 3’-dideoxynucleosides act as chain terminators in retrovirus infections including HIV
= phosphonoformic acid (foscarnet) and phosphonoacetic acid (PAA) – potent highly specific inhibitors of HSV DNA.
= toxic to bones and kidney

19. Antivirals Others methyl phosphonate derivative (s)-HPMPA
= inhibits DNA viruses ex. herpes, pox, adeno and retro
PMEA- for retrovirus, HIV and tumor formation

20. Antivirals Amantadine and Rimantadine
= effective inhibitors of influenza A multiplication
= affects penetration and uncoating
= also inhibits budding and virus particle release
= FDA approved for prophylaxis vs influenza A
= CNS side effects worse for amantadine than rimantadine
= useful for elderlies, immunocompromised, allergies and in epidemics

21. Antivirals Other Antiviral Agents Isatin-B-thiosemicarbazone
= very potent inhibitor of Poxvirus
= at 3 mg/L – inhibits vaccinia multiplication (90%)
= inhibits translation of late mRNA –> no viral capsid and CHON synthesis -> no progeny
Marburan (n-methyl-IBT) – a derivative of IBT
= beneficial effects for smallpox contacts

22. SMALLPOX

23. Antivirals 2-Hydroxylbenzylbenzimidazole (HBB) and Guanidine
= PICORNAVIRUSES (polio, echo, coxsackie and FMD/enteroviruses)
= interfere with replication of viral RNA
= prevent the initiation of the synthesis of progeny (+) strands by inhibiting protein 2C

24. Antivirals Rifampicin and Rifamycin derivatives
= binds to bacterial RNA polymerase
= prevent initiation of transcription
= no binding to animal RNA polymerase
= inhibit multiplication of pox and adeno
= both early and late mRNAs are transcribed
normally (viral polymerase not inhibited)
= accumulation of immature virus particles that lack the normal dense spicule layer

25. Antivirals Arildone, Rhodanine, and WIN 51711
= inhibit uncoating of Picornaviruses by making the virus more stable
= does not affect absorption or penetration

26. Antivirals Inhibitors of Proteases
= precursors do not become the functional
proteins
= HIV protease: essential role in production of a functional virion
= Saquinavir, indinavir, ritonavir, nelfinavir, amprenavir – slip into the hydrophobic active site of the enzyme
= combine with AZT and a 2nd nucleoside analogue in tx of AIDS

27. Antivirals Promising New Approaches Inhibition of Adsorption
= many viral receptors have been identified
Targeted Introduction of Toxins into Infected Cells
= directed against infected cells
= ricin or the Pseudomonas exotoxin to CD4--- attach to gp internalized into infected cell

28. Antivirals
Introduction into Cells of Specific Anti-Sense RNA Sequences
= many mRNA splice junctions have been sequenced
Preventing Interactions Among Protein Molecules
= add excess oligopeptides with the same sequence as that of the interacting sequence

29. Interferons natural antiviral compounds
substances that have antiviral properties in adjacent, noninfected cells
Types of Interferons
Type I: (1) Interferon alpha = maximal
antiviral activity
(2) Interferon Beta = intermediate
Type II: Interferon Gamma = more lymphokine than antiviral

30. Interferons Regulation of Interferon Expression
= not expressed in a normal resting cell
= labile repressors bind to promoter elements, block transcription
= production of labile suppressors drop in viral infection and allows interferon synthesis to occur

31. Interferons Mechanism of action
= synthesis, secretion, diffusion and binding to cellular receptors
= taken up by uninfected cells
= viral replication (-) via cellular enzymes
Type I
= (-) viral protein synthesis (very specific)
= 2 enzymes activated:
1. oligo-A synthetase  adenine nucleotide  viral mRNA digestion
2. protein kinase ->phosphorylates EF-2 -> blocks CHON synthesis
= block other stages of replication including budding

32. Interferons Type II : = antiviral effects mediated by:
1. nitric oxide synthetase—increased intracellular nitric oxide levels
2. upregulation of MHC I and II expression
3. activation of monocytes, macrophages and NK cells

33. Interferon

34. Interferons Clinical Uses: IFN-A :
= treatment of viral infections: condylomata acuminata and chronic hepa B and C
= prophylactic or therapeutic agent in immunocomp. hosts (VZV, HSV 1 and 2)
= prophylaxis vs CMV in renal transplant
= treatment of AIDS-associated Kaposi’s sarcoma and hairy cell leukemia
IFN-G: immunostimulant in oncologic and immunedeficiency disorders

35. Vaccines TYPES OF VACCINES: 1. Inactivated Virus Vaccines
= complete inactivation of infectivity with minimum loss of antigenicity
= ex. a. UV irradiation
b. photodynamic inactivation
and white light irradiation
c. beta-propiolactone
d. formaldehyde (most effective)

36. Vaccines 2. Attenuated Active Virus Vaccines
= Jenner’s smallpox , Theiler’s yellow fever
virus, Sabin poliovirus, MMR, adenovirus
= repeated passage of human pathogens in
other host species
= effective in small amounts: amplification
effect
= recombinant DNA technology has
improved attenuation

37. POLIO VACCINE

38. MEASLES

39. Vaccines 3. Subunit Vaccines = viral proteins that elicit formation
of neutralizing Ab’s
= smaller range of Ab’s (IgA, IgM)
produced
= genes of these CHONs now can be
cloned

40. Vaccines 4. Viral Vectors
= genes of viral CHONs inserted into avirulent
viral vectors
= thymidine kinase gene of Vaccinia virus
= genes are expressed without disease and
Ab’s are produced
= HA gene of influenza, glycoprotein B gene
of herpesvirus, surface Ag of HBV
= major limitation is the infectivity of
vaccinia itself

41. THANK YOU