Download Stages of replication

Antiviral Agents, chapter 39
Different living organisms
Eucaryotes
Mono or polycellular
Cell nucleus; DNA
May have cell wall
sexual and / or asexual replication
Animals
Plants
Fungi
Protocista: - Protozoea
- Algea
Procaryotes
Bakteriea:
Monocellular, no nucleus - DNA single strand,
cell wall, asex. replic.
Virus
RNA or DNA + protein coating (not really a cell)
Use other oramisms ribosomes for protein synth
Stages of replication
DNA or RNA
Protein Coat - Capsid
Protein coat - Envelope
(glycoproteins - antigens, not all viruses)
Many different shapes
May attack:
•Animals
•Plants
•Bacteria (Phages)
Procaryotes and eucaryotes
B
5'
Replication
DNA polymerase
3'
5'
Leading strand
O
Lagging strand
3'
O
HO
5'
DNA
5'
3'
3'
5'
5'
3'
X
B
O P
O
O
O
O
X
O P
O
O
5'
O
HO
(+) stranded RNA
5'
Transcription
3'
RNA polymerase
3'
DNA
3'
5'
DNA
5'
5'
5'
3'
Translation
5'
mRNA
(+) stranded RNA
3'
5'
3'
5'
3'
Protein
B
3'
X
Stages of replication - DNA virus
Attachment, penetration, uncoating, transfer of DNA to cell nucleus
Viral DNA integrated in host DNA
Replication
transcription
translation
mRNA
Viral replication enzymes
Synthesis of more viral DNA
translation
Viral proteins, Capsid etc
Integration of viral proteins
in host cell membrane
Cancer cell
Oncogenic viruses
Assembly
Release:
Budding thru membranes (knoppskyting)
Lysis
Stages of replication - RNA virus
(+) stranded RNA = mRNA
Alternative A: (-) RNA virus
3'
5'
More difficult to treath RNA virus infect.
More mutation - Less repair mech. than with DNA
(-) stranded RNA
Viral RNA replicase
Protein
5'
mRNA
(+) stranded RNA
3'
Alternative B: (+) RNA virus (≠Retrovirus)
5'
3'
Alternative C: Retrovirus; (+) RNA virus
(+) stranded RNA
5'
3'
(+) stranded RNA
Viral RNA replicase
3'
5'
(-) stranded RNA
Viral RNA replicase
5'
3'
5'
3'
5'
(+) stranded RNA
incl. mRNA
3'
3'
5'
5'
3'
(-) DNA strand
Retroviral
Reverse transcriptase
3'
5'
3'
5'
Protein
5'
3'
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)
NH2
•Protease inhibitors
Amantadine
Effect against influenza A viruses
No 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
HO
HO
HO
OH
H
N
CO2H
Glycopeptide
O
O
HO
Neuraminidase
H
N
≈ SN1
HO
O
CO2H
OH
O
OH
+
HO
Glycopeptide
HO
O
Sialic acid
HO
HO
OH
O
H
N
CO2H
HO
HO
O
HO
H
N
OH2
CO2H
OH
Glycopeptide
O
O
HO
Sialic acid
O
≈ TS‡
HO
HO
OH
O
H
N
CO2H
HO
Lead compound Neuramidinase Inhib.
(not selective for viral NA)
Carbocyclic drug
HO
HO
HO
O
First selective drug
HO
OH
O
H
N
CO2H
HO
OH
DANA
CO2H
HN
O
O
O
H
N
HN
NH2
Zanamivir
Relenza®
H O
N
H2N
O
CO2H
Oseltamivir
Tamiflu®
Binding of oseltamivir to NA
H O
N
H2N
O
O
OH
O
HO
O H
N
NH2
O
Hydrophobic pocket
HO
HO
Basic centre better binding than DANA
OH
O
H
N
HO
O
CO2H
DANA
HO
HO
OH
O
H
N
CO2H
HN
O
HN
NH2
Zanamivir
Nucleoside analogs - Antimetabolites
(C.f. anticancer compounds)
O
N
HN
H2N
N
O
N
H
Esterases
N
O
O
Valtrex®
O
Valacyclovir
Increase GI absorbtion
N
HN
H2N
N
N
Aciclovir®
Zovirax®
N
HN
H2N
O
HO
O
N
HO
N
O
Acyclovir
HO
Xanthine oxidase
OH
Guanosine
Adenosine deaminase
N
N
H2N
HO
N
NH2
N
O
6-Deoxyacyclovir
Increased solubility
N
N
H 2N
HO
N
N
O
Guanosine analog
Activity: DNA Herpes viruses
(ex. Herpes simplex, varicella,
cytomegalo, epstein barr)
O
O
N
HN
H2N
HO
N
Viral thymidine kinase
N
H2N
O
N
HN
O
P
Acyclovir
N
Normal
cellular enzymes
N
O
H2N
O
N
HN
N
O
P
P
P
Preference for the viral enzymes
N
O
Viral DNA polymerase
Normal DNA / RNA chain
O
O O
P
O
O
N
HN
O
O
Base
R
R=H in DNA
R=OH in RNA
H2N
DNA Chain
O
P
N
N
O
No 3'OH - No Chain elongation
Relatet Structures
O
O
N
HN
H2N
N
O
N
H
N
O
O
HO
Valgancyclovir
Valcyte®
Esterases
O
N
HN
H2N
N
HN
N
HO
N
O
O,N-acetal
H2N
N
N
Xanthine oxidase
Esterases
Gancyclovir
Cymevene®
H2N
N
N
AcO
HO
HO
N
N
HO
Peniciclovir
More stable
Low oral availability
•Converted to triphosphates
•Inhibitors of viral DNA polymerases
•Gancyclovir: Not dependent of viral thymine kinase
(better effect CMV, EB)
AcO
Famciclovir
Ribavirin
Copegus®
Rebetol®
O
H2N
N
HO
H2N
N
HO
N
O
HO
Cytosine analogs
O
CH3
HN
O
HN
N
O
O
X
Cytarabine (ARA-C)
Cytarabin®, Cytosar®,
N
N
O
O
OH
Thymidine
NH2
R
OH
R = I, X = OH
R = I, X = NH2 (less tox)
R = Br, X = OH
R = F, X = OH
R = CF3, X = OH
HO
NH2
N
N
O
O
OH
OH
HO
N
O
OH
Cytosine
OH
Only cancer ther in N.
Incorp. DNA - faulty viral proteins
OH
Guanosine
OH
Thymidine analogs
O
N
HN
N
O N
HO
HO
O
Guanosine analog
Fosforylated to triphosphate in vivo
Inhib. viral RNA polymerase, RNA / DNA synthesis
Broad spectrum (RNA and DNA viruses, some effect on HIV)
Used against Hepatitis in N., serious side effects
Adenosine analogs
NH2
NH2
N
N
N
HO
HO
N
O
N
N
N
HO
OH
Adenosine
N
O
OH
HO
Isolated Streptomyces antibioticus
First studied as anticancer drug
Interfere with DNA synth
Tox.
Rapid metab. adenosine deaminase
Fludarabine
Fludara®
cancer ther.
NH2
N
N
F
N
N
HO
O
OH
Vidarabine
(Ara-A)
HO
Not good substrate for
adenosine deaminase
Antimetabolite
Other comp. that interfere
with replication
Foscarnet
Foscavir®
Comp. that interfere with translation
Na
O
O P
O
(protein synth)
O
O
Na
Not orally avail.
No in vivo activation required
Inhib. DNA polymerase
Neurotox.
Also active against HIV
Na
Methisazone
N
H
N
S
NH2
O
N
R
One of the oldest antiviral comp. known
Inhib protein synth
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