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ANTIVIRALS, INTERFERON AND VACCINES EDWARD-BENGIE L. MAGSOMBOL, MD, FPCP, FPCC, DASNC Associate Professor in Microbiology 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 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 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 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 Herpes keratoconjunctivitis Herpes simplex Herpes simplex Herpes simplex 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 CHICKENPOX (VARICELLA) 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 CYTOMEGALOVIRUS AIDS Antivirals F. Ribavirin (Virazole) analogue of purine precursor of 5aminoimidazole 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 = RSV infection (bronchiolitis) RESPIRATORY SYNCYTIAL VIRUS 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 Antivirals Others methyl phosphonate derivative (s)-HPMPA = inhibits DNA viruses ex. herpes, pox, adeno and retro PMEA- for retrovirus, HIV and tumor formation 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 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 SMALLPOX 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 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 = Antivirals Arildone, Rhodanine, and WIN 51711 = inhibit uncoating of Picornaviruses by making the virus more stable = does not affect absorption or penetration 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 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 Antivirals = Introduction into Cells of Specific AntiSense 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 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 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 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 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 Interferon 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 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) 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 POLIO VACCINE MEASLES 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 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 THANK YOU