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ANTIVIRALS, ANTIVIRALS, INTERFERON AND INTERFERON AND
VACCINESVACCINES
EDWARD-BENGIE L. MAGSOMBOL, MD, EDWARD-BENGIE L. MAGSOMBOL, MD, FPCP, FPCC, DASNCFPCP, FPCC, DASNC
Assistant Professor in MicrobiologyAssistant Professor in MicrobiologyFatima College of MedicineFatima College of Medicine
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The Viral
Replication Cycle:
Several Important Targets
for Antiviral Therapy
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4 Ways to Combat Viruses:4 Ways to Combat Viruses:
1.1. Immune SystemImmune System
2.2. Antiviral therapyAntiviral therapy
3.3. Interferon therapyInterferon therapy
4.4. VaccinesVaccines
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Viruses treatable with Viruses treatable with antiviralsantivirals
HSVHSVVZVVZVCMVCMVHIVHIV Influenza AInfluenza ARSVRSVHepatitis A, B and C virusesHepatitis A, B and C virusesPapillomavirusPapillomavirusPicornavirusPicornavirus
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AntiviralsAntiviralsAPPROACH TO ANTIVIRAL CHEMOTHERAPYAPPROACH TO ANTIVIRAL CHEMOTHERAPY1. Adsorption, Penetration and Uncoating1. Adsorption, Penetration and Uncoating = little is known about the specific = little is known about the specific
reactions involvedreactions involved = only amantadine, rimantadine used vs = only amantadine, rimantadine used vs
influenza Ainfluenza A = HIV, rhino, EBV now being researched on= HIV, rhino, EBV now being researched on
2. Replication of Viral Nucleic Acids2. Replication of Viral Nucleic Acids = attack enzymes which catalyze replication= attack enzymes which catalyze replication = not present in uninfected cells= not present in uninfected cells = all RNA viruses, pox, herpes and = all RNA viruses, pox, herpes and adenovirusadenovirus
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AntiviralsAntiviralsAPPROACH TO ANTIVIRAL APPROACH TO ANTIVIRAL
CHEMOTHERAPYCHEMOTHERAPY
3.3. Integration of Viral Genomes into Cellular Integration of Viral Genomes into Cellular GenomesGenomes
= as part of multiplication cycle = as part of multiplication cycle (retrovirus and its integrase)(retrovirus and its integrase)
= tumorigenesis (papovavirus, herpes)= tumorigenesis (papovavirus, herpes)
4. Synthesis of Viral Messenger RNA’s4. Synthesis of Viral Messenger RNA’s = virus-encoded RNA polymerases, = virus-encoded RNA polymerases,
capping enzymescapping enzymes
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AntiviralsAntivirals
APPROACH TO ANTIVIRAL APPROACH TO ANTIVIRAL CHEMOTHERAPYCHEMOTHERAPY
5. Synthesis of Viral Proteins5. Synthesis of Viral Proteins
= viral mRNA translation different from = viral mRNA translation different from host mRNAhost mRNA
6. Viral Morphogenesis6. Viral Morphogenesis
= enzymes which cleave precursors for = enzymes which cleave precursors for viral capsid CHONsviral capsid CHONs
= ex. viral proteases= ex. viral proteases
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AntiviralsAntiviralsCLASSES OF ANTIVIRAL AGENTSCLASSES OF ANTIVIRAL AGENTS Synthetic Antiviral AgentsSynthetic Antiviral AgentsI. Analogues of Ribonucleosides and I. Analogues of Ribonucleosides and
DeoxyribonucleosidesDeoxyribonucleosides = nucleic acids base or derivatives= nucleic acids base or derivatives = included into nucleic acid, usually DNA= included into nucleic acid, usually DNA = interfere with nucleic acid function= interfere with nucleic acid function = selectively inhibit viral polymerases= selectively inhibit viral polymerases A. A. Idoxuridine and TrifluorothymidineIdoxuridine and Trifluorothymidine = analogues of thymidine, inhibits viral DNA = analogues of thymidine, inhibits viral DNA
formationformation = inhibit multiplication of herpesviruses= inhibit multiplication of herpesviruses = used for topical treatment of herpes simplex = used for topical treatment of herpes simplex keratitiskeratitis = not for systemic use because of toxicity= not for systemic use because of toxicity
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Herpes keratoconjunctivitisHerpes keratoconjunctivitis
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Herpes simplexHerpes simplex
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Herpes simplexHerpes simplex
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Herpes simplexHerpes simplex
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AntiviralsAntiviralsB. Vidarabine (Adenosine arabinoside, Ara-B. Vidarabine (Adenosine arabinoside, Ara-
A)A) = inhibits HSV and VZV multiplication= inhibits HSV and VZV multiplication = act as chain terminators; inhibit viral DNA = act as chain terminators; inhibit viral DNA
polymerase more than host DNA polymerasepolymerase more than host DNA polymerase = herpes simplex keratitis; herpes simplex = herpes simplex keratitis; herpes simplex
encephalitis (IV route)encephalitis (IV route)C. Acyclovir, FamciclovirC. Acyclovir, Famciclovir
= guanine linked to an open ring analogue of = guanine linked to an open ring analogue of ribose, deoxyriboseribose, deoxyribose
= thymine or cytosine derivative= thymine or cytosine derivative = phosphorylated by HSV and VZV TKinases= phosphorylated by HSV and VZV TKinases = topical or IV in mucocutaneous herpes simplex = topical or IV in mucocutaneous herpes simplex
in immunocompromised hosts and also in in immunocompromised hosts and also in genital genital
herpes simplex infectionsherpes simplex infections
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CHICKENPOX (VARICELLA)CHICKENPOX (VARICELLA)
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AntiviralsAntiviralsD. GanciclovirD. Ganciclovir= = close relative of acyclovir; inhibits close relative of acyclovir; inhibits
HSV multiplicationHSV multiplication = better substrate for HSV TK than = better substrate for HSV TK than
acycloviracyclovir = best inhibitor of CMV multiplication in = best inhibitor of CMV multiplication in
useuse = probably not a strict chain terminator = probably not a strict chain terminator
unlike acyclovirunlike acyclovir
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AntiviralsAntiviralsE. Zidovudine (Azidothymidine, AZT, E. Zidovudine (Azidothymidine, AZT,
RetrovirRetrovir))= inhibits retrovirus reverse transcriptase (RT)= inhibits retrovirus reverse transcriptase (RT)= chain terminator because it does not possess a = chain terminator because it does not possess a
3’-OH group3’-OH group= demonstrated clinical efficacy in HIV = demonstrated clinical efficacy in HIV = others: zalcitabine, didanosine, stavudine, = others: zalcitabine, didanosine, stavudine,
lamivudinelamivudine nevirapine nevirapine = lamivudine: newer generation RT inhibitor = lamivudine: newer generation RT inhibitor
effective vs hepatitis Beffective vs hepatitis B= new antivirals that don’t look like nucleosides = new antivirals that don’t look like nucleosides
but still block RTbut still block RT
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CYTOMEGALOVIRUSCYTOMEGALOVIRUS
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AIDSAIDS
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AntiviralsAntiviralsF. Ribavirin (Virazole)F. Ribavirin (Virazole)= = analogue of purine precursor of 5-analogue of purine precursor of 5-
aminoimidazole 4-carboxamideaminoimidazole 4-carboxamide
= wide spectrum: good vs RNA and DNA viruses= wide spectrum: good vs RNA and DNA viruses
= target: virus-encoded nucleic acid = target: virus-encoded nucleic acid polymerasespolymerases
= affects elongation and initiation (less extent)= affects elongation and initiation (less extent)
= for severe RSV infection (aerosol) in children= for severe RSV infection (aerosol) in children
= reduce mortality on patients with Lassa fever= reduce mortality on patients with Lassa fever
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RSV RSV infectioninfection
(bronchiolitis(bronchiolitis
))
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RESPIRATORY SYNCYTIAL RESPIRATORY SYNCYTIAL VIRUS VIRUS
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AntiviralsAntivirals
OthersOthers= analogues of thymidine = analogues of thymidine (BVdU)(BVdU) and and
cytosine cytosine (FIAC)(FIAC) - good vs herpesvirus - good vs herpesvirus DNA polymerases with low toxicityDNA polymerases with low toxicity
= 2’, 3’-dideoxynucleosides act as chain = 2’, 3’-dideoxynucleosides act as chain terminators in retrovirus infections terminators in retrovirus infections including HIVincluding HIV
= phosphonoformic acid = phosphonoformic acid (foscarnet)(foscarnet) and and phosphonoacetic acid phosphonoacetic acid (PAA)(PAA) – potent – potent highly specific inhibitors of HSV DNA.highly specific inhibitors of HSV DNA.
= toxic to bones and kidney= toxic to bones and kidney
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AntiviralsAntivirals
OthersOthers
methyl phosphonate derivative (s)-methyl phosphonate derivative (s)-HPMPA HPMPA
= inhibits DNA viruses ex. herpes, = inhibits DNA viruses ex. herpes, pox, adeno and retropox, adeno and retro
PMEAPMEA- for retrovirus, HIV and tumor - for retrovirus, HIV and tumor formationformation
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AntiviralsAntiviralsAmantadine and RimantadineAmantadine and Rimantadine= = effective inhibitors of influenza A effective inhibitors of influenza A
multiplication; bind to and block H channelmultiplication; bind to and block H channel and prevent M1 proteins from dissociatingand prevent M1 proteins from dissociating from nucleocapsidfrom nucleocapsid= affects penetration and uncoating= affects penetration and uncoating= also inhibits budding and virus particle = also inhibits budding and virus particle
releaserelease= FDA approved for prophylaxis vs influenza A= FDA approved for prophylaxis vs influenza A= CNS side effects worse for amantadine than = CNS side effects worse for amantadine than
rimantadinerimantadine= useful for elderly, immunocompromised, = useful for elderly, immunocompromised,
allergies and in epidemicsallergies and in epidemics
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AntiviralsAntivirals
Pleconaril= inhibits uncoating of Pleconaril= inhibits uncoating of rhinovirus by blocking a pocket on rhinovirus by blocking a pocket on the viral surface which controls the the viral surface which controls the uncoating processuncoating process
Same pocket is found among Same pocket is found among enterovirusesenteroviruses
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AntiviralsAntivirals
Other Antiviral AgentsOther Antiviral Agents Isatin-B-thiosemicarbazoneIsatin-B-thiosemicarbazone= very potent inhibitor of Poxvirus= very potent inhibitor of Poxvirus
= at 3 mg/L – inhibits vaccinia multiplication = at 3 mg/L – inhibits vaccinia multiplication (90%)(90%)
= inhibits translation of late mRNA –> no viral = inhibits translation of late mRNA –> no viral capsid and CHON synthesis -> no progenycapsid and CHON synthesis -> no progeny
Marburan (n-methyl-IBT)Marburan (n-methyl-IBT) – a derivative of – a derivative of IBTIBT
= beneficial effects for smallpox contacts= beneficial effects for smallpox contacts
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SMALLPOXSMALLPOX
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AntiviralsAntivirals
2-2-HydroxylbenzylbenzimidazoHydroxylbenzylbenzimidazole (HBB) and Guanidinele (HBB) and Guanidine
= PICORNAVIRUSES (polio, echo, = PICORNAVIRUSES (polio, echo, coxsackie and coxsackie and FMD/enteroviruses)FMD/enteroviruses)
= interfere with replication of = interfere with replication of viral RNAviral RNA
= prevent the initiation of the = prevent the initiation of the synthesis of progeny (+) synthesis of progeny (+) strands by inhibiting protein 2Cstrands by inhibiting protein 2C
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AntiviralsAntiviralsRifampicin and Rifamycin derivativesRifampicin and Rifamycin derivatives= = binds to bacterial RNA polymerasebinds to bacterial RNA polymerase
= prevent initiation of transcription= prevent initiation of transcription
= no binding to animal RNA polymerase= no binding to animal RNA polymerase
= inhibit multiplication of pox and adeno = inhibit multiplication of pox and adeno
= both early and late mRNAs are transcribed = both early and late mRNAs are transcribed
normally (viral polymerase not inhibited)normally (viral polymerase not inhibited)
= accumulation of immature virus particles = accumulation of immature virus particles that lack the normal dense spicule layer that lack the normal dense spicule layer
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AntiviralsAntivirals
Arildone, Rhodanine, and Arildone, Rhodanine, and WIN 51711WIN 51711
= inhibit uncoating of = inhibit uncoating of Picornaviruses by making the Picornaviruses by making the virus more stable virus more stable
= does not affect absorption or = does not affect absorption or penetrationpenetration
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AntiviralsAntivirals
Translation: AntisenseTranslation: Antisense= segments of DNA or RNA that = segments of DNA or RNA that
act as mirror images to critical act as mirror images to critical sections of viral genomessections of viral genomes
= fomivirsen: for CMV eye = fomivirsen: for CMV eye infections in AIDS patientsinfections in AIDS patients
= morpholino antisense: = morpholino antisense: experimentally suppress the ff:experimentally suppress the ff:
calicivirus, flavivirus, dengue, calicivirus, flavivirus, dengue, HCV, coronavirusesHCV, coronaviruses
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AntiviralsAntivirals
Translation: RibozymesTranslation: Ribozymes= enzymes that cut apart viral DNA or RNA= enzymes that cut apart viral DNA or RNA
= ongoing work on Hepa C and HIV= ongoing work on Hepa C and HIV
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AntiviralsAntiviralsInhibitors of ProteasesInhibitors of Proteases= precursors do not become the = precursors do not become the
functional functional
proteins; synthetic peptidesproteins; synthetic peptides
= (-) = (-) HIV protease:HIV protease: essential role in essential role in production of a functional virionproduction of a functional virion
= Saquinavir, indinavir, ritonavir, = Saquinavir, indinavir, ritonavir, nelfinavir, amprenavir – slip into the nelfinavir, amprenavir – slip into the hydrophobic active site of the hydrophobic active site of the enzymeenzyme
= combine with AZT and a 2= combine with AZT and a 2ndnd nucleoside analogue in tx of AIDSnucleoside analogue in tx of AIDS
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AntiviralsAntiviralsInhibitors of Viral releaseInhibitors of Viral release= final stage is the release of the = final stage is the release of the
completed virus from the host cellcompleted virus from the host cell
= zanamivir (Relenza) and oseltamivir = zanamivir (Relenza) and oseltamivir (Tamiflu) block neuraminidase in the (Tamiflu) block neuraminidase in the surface of influenza virussurface of influenza virus
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AntiviralsAntiviralsPromising New ApproachesPromising New Approaches Inhibition of AdsorptionInhibition of Adsorption
= many viral receptors have been = many viral receptors have been identifiedidentified
Targeted Introduction of Toxins into Targeted Introduction of Toxins into Infected CellsInfected Cells
= directed against infected cells= directed against infected cells
= ricin or the Pseudomonas exotoxin = ricin or the Pseudomonas exotoxin to CD4--- attach to gp120 --- to CD4--- attach to gp120 --- internalized into infected cellinternalized into infected cell
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AntiviralsAntivirals
Introduction into Cells of Specific Introduction into Cells of Specific Anti-Sense RNA SequencesAnti-Sense RNA Sequences
= = many mRNA splice junctions have many mRNA splice junctions have been sequencedbeen sequenced
Preventing Interactions Among Preventing Interactions Among Protein MoleculesProtein Molecules
= = add excess oligopeptides with the add excess oligopeptides with the same sequence as that of the same sequence as that of the interacting sequenceinteracting sequence
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InterferonsInterferons natural antiviral compoundsnatural antiviral compounds substances that have antiviral properties substances that have antiviral properties
in adjacent, noninfected cellsin adjacent, noninfected cells
Types of InterferonsTypes of Interferons
Type I:Type I: (1) Interferon alpha (1) Interferon alpha = maximal = maximal
antiviral activityantiviral activity
(2) Interferon Beta(2) Interferon Beta = intermediate = intermediate
antiviral activityantiviral activity
Type II:Type II: Interferon GammaInterferon Gamma = more = more lymphokine than antivirallymphokine than antiviral
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InterferonsInterferonsRegulation of Interferon Regulation of Interferon
ExpressionExpression= not expressed in a normal resting = not expressed in a normal resting
cellcell
= labile repressors bind to = labile repressors bind to promoter elements, block promoter elements, block transcriptiontranscription
= production of labile suppressors = production of labile suppressors drop in viral infection and allows drop in viral infection and allows interferon synthesis to occurinterferon synthesis to occur
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InterferonsInterferonsMechanism of actionMechanism of action= synthesis, secretion, diffusion and binding = synthesis, secretion, diffusion and binding
to cellular receptorsto cellular receptors
= taken up by uninfected cells= taken up by uninfected cells
= viral replication (-) via cellular enzymes = viral replication (-) via cellular enzymes
Type IType I
= (-) viral protein synthesis (very specific)= (-) viral protein synthesis (very specific)
= 2 enzymes activated:= 2 enzymes activated:
1. 1. oligo-A synthetaseoligo-A synthetase adenine nucleotide adenine nucleotide viral mRNA digestion viral mRNA digestion
2. protein kinase2. protein kinase ->phosphorylates EF-2 -> ->phosphorylates EF-2 -> blocks CHON synthesisblocks CHON synthesis
= block other stages of replication including = block other stages of replication including buddingbudding
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InterferonsInterferons
Type II :Type II :
= antiviral effects mediated by:= antiviral effects mediated by:
1. nitric oxide synthetase—1. nitric oxide synthetase—increased intracellular nitric increased intracellular nitric oxide levels oxide levels
2. upregulation of MHC I and II 2. upregulation of MHC I and II expressionexpression
3. activation of monocytes, 3. activation of monocytes, macrophages and NK cellsmacrophages and NK cells
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InterferonInterferon
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InterferonsInterferonsClinical Uses:Clinical Uses: IFN-A :IFN-A :
= treatment of viral infections: = treatment of viral infections: condylomata acuminata and chronic hepa condylomata acuminata and chronic hepa B and CB and C
= prophylactic or therapeutic agent in = prophylactic or therapeutic agent in immunocomp. hosts (VZV, HSV 1 and 2)immunocomp. hosts (VZV, HSV 1 and 2)
= prophylaxis vs CMV in renal transplant= prophylaxis vs CMV in renal transplant
= treatment of AIDS-associated Kaposi’s = treatment of AIDS-associated Kaposi’s sarcoma and hairy cell leukemiasarcoma and hairy cell leukemia
IFN-G:IFN-G: immunostimulant in oncologic and immunostimulant in oncologic and immunedeficiency disordersimmunedeficiency disorders
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Sites for Sites for effective effective action of action of various various AntiviralsAntivirals
versus versus VirusesViruses
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VaccinesVaccines
TYPES OF VACCINES:TYPES OF VACCINES: 1. Inactivated Virus Vaccines1. Inactivated Virus Vaccines = complete inactivation of = complete inactivation of
infectivity with minimum loss of infectivity with minimum loss of antigenicityantigenicity
= ex. a. UV irradiation= ex. a. UV irradiation b. photodynamic inactivation b. photodynamic inactivation and white light and white light
irradiationirradiation c. beta-propiolactonec. beta-propiolactone d. formaldehyde (most d. formaldehyde (most
effective)effective)
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VaccinesVaccines
2.2. Attenuated Active Virus VaccinesAttenuated Active Virus Vaccines = Jenner’s smallpox , Theiler’s yellow fever = Jenner’s smallpox , Theiler’s yellow fever
virus, Sabin poliovirus, MMR, adenovirusvirus, Sabin poliovirus, MMR, adenovirus
= repeated passage of human pathogens in = repeated passage of human pathogens in
other host speciesother host species
= effective in small amounts: amplification = effective in small amounts: amplification
effect effect
= recombinant DNA technology has = recombinant DNA technology has
improved attenuationimproved attenuation
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POLIO VACCINEPOLIO VACCINE
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MEASLESMEASLES
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VaccinesVaccines
3. Subunit Vaccines3. Subunit Vaccines
= viral proteins that elicit = viral proteins that elicit formation formation
of neutralizing Ab’sof neutralizing Ab’s
= smaller range of Ab’s (IgA, IgM) = smaller range of Ab’s (IgA, IgM)
producedproduced
= genes of these CHONs now can = genes of these CHONs now can be be
clonedcloned
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VaccinesVaccines4. Viral Vectors4. Viral Vectors = genes of viral CHONs inserted into = genes of viral CHONs inserted into
avirulent avirulent
viral vectorsviral vectors
= thymidine kinase gene of Vaccinia virus = thymidine kinase gene of Vaccinia virus
= genes are expressed without disease and = genes are expressed without disease and
Ab’s are producedAb’s are produced
= HA gene of influenza, glycoprotein B gene = HA gene of influenza, glycoprotein B gene
of herpesvirus, surface Ag of HBVof herpesvirus, surface Ag of HBV
= major limitation is the infectivity of = major limitation is the infectivity of
vaccinia itselfvaccinia itself
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