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
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 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
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 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
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