Antiviral Agents, chapter 43 Different living organisms Virus Procaryotes Eucaryotes Bakteriea: Monocellular, no nucleus - DNA single strand, cell wall, asex. replic. Mono or polycellular Cell nucleus; DNA May have cell wall sexual and / or asexual replication Animals Plants Fungi Protocista: - Protozoea - Algea RNA or DNA + protein coating (not really a cell) Use other oramisms ribosomes for protein synth
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Antiviral Agents, chapter 43 - Universitetet i oslo...Antiviral Agents, chapter 43 Different living organisms Virus Procaryotes Eucaryotes Bakteriea: Monocellular, no nucleus - DNA
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Antiviral Agents, chapter 43
Different living organisms
Virus
Procaryotes
Eucaryotes
Bakteriea: Monocellular, no nucleus - DNA single strand, cell wall, asex. replic.
Mono or polycellularCell nucleus; DNAMay have cell wallsexual and / or asexual replication
Animals
Plants
Fungi
Protocista: - Protozoea - Algea
RNA or DNA + protein coating (not really a cell)Use other oramisms ribosomes for protein synth
Many different shapes
Stages of replicationDNA or RNA
Protein Coat - Capsid
Protein coat - Envelope (glycoproteins - antigens, not all viruses)
May attack:•Animals•Plants•Bacteria (Phages)
OO
XHO
B
P
OO
XO
B
P
OO
OHO
XO
B
OO
5'
3'
DNA
Procaryotes and eucaryotes
5'
5'3'
3'
Leading strandLagging strand
3' 5'
5' 3'
3' 5'
3'5'
Replication
Transcription
DNA polymerase
DNA
5'
5'3'RNA polymerase
DNA
5'
5'3'
3'5'
(+) stranded RNA
Translation
mRNA(+) stranded RNA
3'5'
Protein
3'5'
3'5'
Stages of replication - DNA virus
Attachment, penetration, uncoating, transfer of DNA to cell nucleus
Viral DNA integrated in host DNAReplication
Synthesis of more viral DNA
transcription
mRNA
translation
Viral proteins, Capsid etc
translationViral replication enzymes
Integration of viral proteins in host cell membrane
Antiviral Drugs•Amantadine and analogs•Neuraminidase Inhibitors•Nucleoside analogs - Antimetabolites•Other comp. that interfere with replication•Comp. that interfere with translation (protein synth)•Interferon / interferon inducers
Specific retroviral drugs•Reverse transcriptase inhibitors
Nucleosides (NRTIs)Non-nucleosides (NNRTIs)
•Protease inhibitorsNH2
Amantadine
Effect against influenza A virusesNo longer in use N.•Inhib. penetration of RNA virus•Inhib. uncoting
Neuraminidase InhibitorsEffect on influenza virus A and B(?)
Inhib. neuraminidase
(enzyme that breaks bonds between HA* in newly HA in formed virus and host cell)
Prevents release of virus
HA: Hemaglutinin, (glycoprotein)important for bonding between influenza virus and host
O
CO2H
O Glycopeptide
HO
HN
O
OHHO
HO
NeuraminidaseHO GlycopeptideO
CO2H
OHHO
HN
O
OHHO
HO
+
Sialic acid≈ SN1
≈ TS‡
ZanamivirRelenza®
OseltamivirTamiflu®(“Take my flu”)
O
CO2H
O Glycopeptide
HO
HN
O
OHHO
HO
Sialic acid
OCO2HHO
HN
O
OHHO
HO
OH2
OCO2HHO
HN
O
OHHO
HO
Lead compound Neuramidinase Inhib. (not selective for viral NA)
•Converted to triphosphates•Inhibitors of viral DNA polymerases
•Gancyclovir: Not dependent of viral thymine kinase (better effect CMV, EB)
O NHO
OHHO
NN
OH2N
RibavirinCopegus®Rebetol®
Guanosine analogFosforylated to triphosphate in vivoInhib. viral RNA polymerase, RNA / DNA synthesisBroad spectrum (RNA and DNA viruses, some effect on HIV)Used against Hepatitis in N., serious side effects
HN
N N
NO
H2N OHO
OHHO
Guanosine
Thymidine analogs
R = I, X = OHR = I, X = NH2 (less tox)R = Br, X = OHR = F, X = OHR = CF3, X = OH
Incorp. DNA - faulty viral proteins
Cytosine analogs
Cytarabine (ARA-C)Cytarabin®, Cytosar®,
Only cancer ther in N.
HN
N
O
O
CH3
OHO
OHThymidine
HN
N
O
O
R
OX
OH
N
N
NH2
OO
HO
OH
Cytosine
OH
N
N
NH2
OO
HO
OH
OH
Adenosine analogsFludarabineFludara® cancer ther.
N
N N
NNH2
OHO
OHHO
Adenosine
Isolated Streptomyces antibioticusFirst studied as anticancer drugInterfere with DNA synthTox.Rapid metab. adenosine deaminase
N
N N
NNH2
OHOOH
HO
F
Antimetabolite
Not good substrate for adenosine deaminase
N
N N
NNH2
OHO OH
HO
Vidarabine (Ara-A)
Other comp. that interfere with replication
FoscarnetFoscavir®
PO
OO
O
O Na
Na
Na
Not orally avail.No in vivo activation requiredInhib. DNA polymeraseNeurotox.Also active against HIV
Comp. that interfere with translation (protein synth)
One of the oldest antiviral comp. knownInhib protein synth
MethisazoneNR
O
NHN S
NH2
Interferon / interferon inducers
Interferon:•Rel small glycoproteins formed in virus infected cells (leukocytes, fibroblasts)•Binds to surphase of other cells •Initiates events leading to inhib. of mRNA trascrib. and translation•Host spesific (not virus spesific)