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Hey guys....sorry for the delay...I just got the ppt now since I did not come home for lunch...

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Antivirals, interferon and vaccines lect copy Presentation Transcript

  • 1. ANTIVIRALS, INTERFERON AND VACCINES EDWARD-BENGIE L. MAGSOMBOL, MD, FPCP, FPCC, DASNC Assistant Professor in Microbiology Fatima College of Medicine
  • 2. The Viral Replication Cycle: Several Important Targets for Antiviral Therapy
  • 3. 4 Ways to Combat Viruses:
    • Immune System
    • Antiviral therapy
    • Interferon therapy
    • Vaccines
  • 4. Viruses treatable with antivirals
    • HSV
    • VZV
    • CMV
    • HIV
    • Influenza A
    • RSV
    • Hepatitis A, B and C viruses
    • Papillomavirus
    • Picornavirus
  • 5. 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
  • 6. 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
  • 7. 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
  • 8. 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 for systemic use because of toxicity
  • 9. Herpes keratoconjunctivitis
  • 10. Herpes simplex
  • 11. Herpes simplex
  • 12. Herpes simplex
  • 13. 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, Famciclovir
    • = 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
  • 14. CHICKENPOX (VARICELLA)
  • 15. 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
  • 16. Antivirals
            • E. Zidovudine (Azidothymidine, AZT, Retrovir )
        • = inhibits retrovirus reverse transcriptase (RT)
        • = chain terminator because it does not possess a 3’-OH group
        • = demonstrated clinical efficacy in HIV
        • = others: zalcitabine, didanosine, stavudine, lamivudine
        • nevirapine
        • = lamivudine: newer generation RT inhibitor effective vs hepatitis B
        • = new antivirals that don’t look like nucleosides but still block RT
  • 17. CYTOMEGALOVIRUS
  • 18. AIDS
  • 19. 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
  • 20. RSV infection (bronchiolitis )
  • 21. RESPIRATORY SYNCYTIAL VIRUS
  • 22. 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
  • 23. Antivirals
            • Others
            • methyl phosphonate derivative (s)-HPMPA
            • = inhibits DNA viruses ex. herpes, pox, adeno and retro
            • PMEA - for retrovirus, HIV and tumor formation
  • 24. Antivirals
            • Amantadine and Rimantadine
            • = effective inhibitors of influenza A multiplication; bind to and block H channel
            • and prevent M1 proteins from dissociating
            • from nucleocapsid
            • = 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 elderly, immunocompromised, allergies and in epidemics
  • 25. Antivirals
    • Pleconaril= inhibits uncoating of rhinovirus by blocking a pocket on the viral surface which controls the uncoating process
    • Same pocket is found among enteroviruses
  • 26. 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
  • 27. SMALLPOX
  • 28. 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
  • 29. 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
  • 30. Antivirals
            • Arildone, Rhodanine, and WIN 51711
            • = inhibit uncoating of Picornaviruses by making the virus more stable
            • = does not affect absorption or penetration
  • 31. Antivirals
            • Translation: Antisense
            • = segments of DNA or RNA that act as mirror images to critical sections of viral genomes
            • = fomivirsen: for CMV eye infections in AIDS patients
            • = morpholino antisense: experimentally suppress the ff:
            • calicivirus, flavivirus, dengue, HCV, coronaviruses
  • 32. Antivirals
            • Translation: Ribozymes
            • = enzymes that cut apart viral DNA or RNA
            • = ongoing work on Hepa C and HIV
  • 33. Antivirals
            • Inhibitors of Proteases
            • = precursors do not become the functional
            • proteins; synthetic peptides
            • = (-) 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 2 nd nucleoside analogue in tx of AIDS
  • 34. Antivirals
            • Inhibitors of Viral release
            • = final stage is the release of the completed virus from the host cell
            • = zanamivir (Relenza) and oseltamivir (Tamiflu) block neuraminidase in the surface of influenza virus
  • 35. 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 gp120 --- internalized into infected cell
  • 36. 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
  • 37. 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
            • antiviral activity
            • Type II: Interferon Gamma = more lymphokine than antiviral
  • 38. 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
  • 39. 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
  • 40. 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
  • 41. Interferon
  • 42. 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
  • 43.
    • Sites for effective action of various Antivirals
    • versus Viruses
  • 44. 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)
  • 45. 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
  • 46. POLIO VACCINE
  • 47. MEASLES
  • 48. 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
  • 49. 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
  • 50. THANK YOU