Transcript ANTIVIRALS, INTERFERON AND VACCINES

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
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Synthetic Antiviral Agents
I. Analogues of Ribonucleosides and Deoxyribonucleosides
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nucleic acids base or derivatives
included into nucleic acid, usually DNA
interfere with nucleic acid function
selectively inhibit viral polymerases
A. Idoxuridine and Trifluorothymidine
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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
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RSV
infection
(bronchiolitis)
RESPIRATORY SYNCYTIAL VIRUS
Antivirals
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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
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Antivirals
Amantadine and Rimantadine
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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
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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
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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
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Inhibition of Adsorption
= many viral receptors have been identified
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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
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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
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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
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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