antiviral agents, chapter 39 different living organisms
TRANSCRIPT
Antiviral Agents, chapter 39
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
O
O
OHO
XO
B
O
O
5'
3'
DNA
Procaryotes and eucaryotes
5'
5'3'
3'
Leading strand
Lagging strand
3' 5'
5' 3'
3' 5'
3'5'
Replication
Transcription
DNA polymerase
DNA
5'
5'3'
RNA polymeraseDNA
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 DNA
Replication
Synthesis of more viral DNA
transcription
mRNA
translation
Viral proteins, Capsid etc
translationViral replication enzymes
Integration of viral proteins in host cell membrane
Cancer cell
AssemblyRelease: Budding thru membranes (knoppskyting) Lysis
Oncogenic viruses
Stages of replication - RNA virus
More difficult to treath RNA virus infect.More mutation - Less repair mech. than with DNA
(+) stranded RNA = mRNA
Alternative A: (-) RNA virus
5'3'(-) stranded RNA
Viral RNA replicase
3'5'
mRNA(+) stranded RNA
Protein
Alternative B: (+) RNA virus (≠Retrovirus)
(+) stranded RNA3'5'
5'3'(-) stranded RNA
Viral RNA replicase
3'5'
(+) stranded RNAincl. mRNA
Protein
Viral RNA replicase
3'5'
3'5'
Alternative C: Retrovirus; (+) RNA virus
3' 5'
3'5'
(+) stranded RNA3'5'
Retroviral Reverse transcriptase
3'5'
(-) DNA strand
3' 5'
3' 5'Further replication as a DNA virus
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 Inhibitors
Effect 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
OGlycopeptide
HO
HN
O
OHHO
HO
NeuraminidaseHO
GlycopeptideO
CO2H
OHHO
HN
O
OHHO
HO
+
Sialic acid≈ SN1
≈ TS‡
ZanamivirRelenza®
OseltamivirTamiflu®
O
CO2H
OGlycopeptide
HO
HN
O
OHHO
HO
Sialic acid
OCO2H
HO
HN
O
OHHO
HO
OH2
O
CO2HHO
HN
O
OHHO
HO
Lead compound Neuramidinase Inhib. (not selective for viral NA)
DANA
First selective drug Carbocyclic drug
CO2HH2N
HN
O
OO
CO2HHO
HN
O
OHHO
HO
O
CO2HHN
HN
O
OHHO
HO
HN NH2
Binding of oseltamivir to NAH2N
HN
O
O O
OH NH2
HN
O
OO
HO
Basic centre better binding than DANA
Hydrophobic pocket
DANA
O
CO2HHO
HN
O
OHHO
HO
Zanamivir
O
CO2HHN
HN
O
OHHO
HO
HN NH2
Nucleoside analogs - Antimetabolites
(C.f. anticancer compounds)
HN
N N
N
O
H2NO
HO
OHHO
Guanosine
Aciclovir®Zovirax®Valtrex®
Guanosine analogActivity: DNA Herpes viruses(ex. Herpes simplex, varicella, cytomegalo, epstein barr)
HN
N N
N
O
H2NO
HO
Acyclovir
HN
N N
N
O
H2NO
O
Valacyclovir
ONH
Increase GI absorbtion
N
N N
N
H2NO
HO
6-Deoxyacyclovir
Esterases
Increased solubility
Xanthine oxidase
Adenosine deaminase
N
N N
N
H2NO
HO
NH2
HN
N N
N
O
H2NO
HO
Acyclovir
Viral thymidine kinase HN
N N
N
O
H2NO
O
P
Normal cellular enzymes
HN
N N
N
O
H2NO
O
P
P
P
Viral DNA polymerase
HN
N N
N
O
H2NO
O
PDNA Chain
No 3'OH - No Chain elongation
Preference for the viral enzymes
O BaseO
RO
POO
O
R=H in DNAR=OH in RNA
Normal DNA / RNA chain
Relatet Structures
HN
N N
N
O
H2NO
HO
Gancyclovir
HN
N N
N
O
H2NO
O
Valgancyclovir
ONH
Esterases
HOHO
O,N-acetal
Cymevene®Valcyte®
HN
N N
N
O
H2N
HO
Peniciclovir
HO
More stableLow oral availability
Xanthine oxidaseEsterases
N
N N
N
H2N
AcO
Famciclovir
AcO
•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
N
O
H2NO
HO
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
OH
Thymidine
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
N
NH2
OHO
OHHO
Adenosine
Isolated Streptomyces antibioticusFirst studied as anticancer drugInterfere with DNA synthTox.Rapid metab. adenosine deaminase
N
N N
N
NH2
OHO
OH
HO
F
Antimetabolite
Not good substrate for adenosine deaminase
N
N N
N
NH2
OHO OH
HO
Vidarabine (Ara-A)
Other comp. that interfere
with replication
FoscarnetFoscavir®
P
O
O
O
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
Methisazone
N
R
O
N
HN 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)
Interferon Inducers
•Double stranded RNA•Heparin•Dextranes•Other bioplolymers •Tilorone
Side effects
O
O
N
O
N