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
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 = mRNAAlternative 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 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)
DANA
First selective drug Carbocyclic drug
CO2HH2N
HN
O
OOCO2HHO
HN
O
OHHO
HO
OCO2HHN
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
OCO2HHO
HN
O
OHHO
HO
Zanamivir
OCO2HHN
HN
O
OHHO
HO
HN NH2
Nucleoside analogs - Antimetabolites
(C.f. anticancer compounds)
HN
N N
NO
H2N OHO
OHHO
Guanosine
Aciclovir®Zovirax®Valtrex®
Guanosine analogActivity: DNA Herpes viruses(ex. Herpes simplex, varicella, cytomegalo, epstein barr)
HN
N N
NO
H2N OHO
Acyclovir
HN
N N
NO
H2N OO
Valacyclovir
ONH
Increase GI absorbtion
N
N N
N
H2N OHO
6-Deoxyacyclovir
Esterases
Increased solubility
Xanthine oxidaseAdenosine deaminase
N
N N
N
H2N OHO
NH2
HN
N N
NO
H2N OHO
Acyclovir
Viral thymidine kinase HN
N N
NO
H2N OOP
Normal cellular enzymes HN
N N
NO
H2N OOPPP
Viral DNA polymerase
HN
N N
NO
H2N OOPDNA 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
NO
H2N OHO
Gancyclovir
HN
N N
NO
H2N OO
Valgancyclovir
ONH
Esterases
HOHO
O,N-acetal
Cymevene®Valcyte®
HN
N N
NO
H2NHO
PeniciclovirHO
More stableLow oral availability
Xanthine oxidaseEsterases
N
N N
N
H2NAcO
FamciclovirAcO
•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)
Interferon Inducers
•Double stranded RNA•Heparin•Dextranes•Other bioplolymers •Tilorone
Side effects
O
ON
ON
Retrovirus HIV (humans) Animal viruses resulting in cancer / AIDS
15-39%
http://www.who.int/hiv/facts/hiv2003/en/
OO
XHO
B
P
OO
XO
B
P
OO
OHO
XO
B
OO
5'
3'
3' 5'
3'5'
(+) stranded RNA3'5'
Retroviral Reverse transcriptase
3'5'(-) DNA strand
3' 5'
3' 5'Further replication as a DNA virus
Stages of replication - RNA virus
Alternative C: Retrovirus; (+) RNA virus
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'
Specific retroviral drugs•Reverse transcriptase inhibitors
Nucleosides (NRTIs)Non-nucleosides (NNRTIs)
•Protease inhibitors
Nucleoside Reverse Transcriptase Inhibitors
Nucleoside analogs without 3’ OH - DNA chain terminationPro-drugs - Phosphorylated by kinases in vivo
HN
NO
O
O
HO
N3
Zidovudine (AZT)Retrovir®Trizivir® Kombi prep.
HN
NO
O
O
HO
StavudineZerit®
N
NO
O
NH2
HO
Zalcitabine (ddC)
N
NO
S
O
NH2
HO
Higher bioavail. than ddC
Lamividine (3TC)Epivir®Trizivir® Compivir ® Kombi prep.
Didanosine (ddI)Videx®
HN
N N
NO
OHO
in vivo N
N N
NNH2
OOPPPN
N N
NHN
HOH2N
Abacavir (ABC)Trizivir® Kombi prep.
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)
Efavirenz / SustivaStocrin®
NH
N NN
MeO
NevirapinViramune®
O
NH
Cl
O
F3C
NH
X
O
O
X=Cl, F
J Med Chem 2004, 5923
FDA 1998Already resistance
activity resist strains Wild type RT mutated
Binds directly to TR
Protease Inhibitors
The HIV-1 protease is an enzyme crucial for the maturation and assembly of infectious viral particles
3'5'
Translation
mRNA(+) stranded RNA
3'5'
Protein(from gag ang gag-pol genes)
3'5'
HIV proptease(Aspartase)
Mature functional proteins
Virus assemply
Science 1990, 249, 527
The two subunits are rotated 180 from each other
J . Med. Chem. 1990,33, 2687
Design of C2 sym. comp. as TS(Intermed) analog of Phe-Pro cleavage
(Type 1 comp. did not lead to drugs)
X-ray: HIV-1 protease - C2 symmetric homodimeric -Not C2-sym. in related human proteases!
OHN N
H
HN N
OH
PhO
S
N
PhO
ON
SRitonavirNorvir®
HO OH
NH2H2N
PhPh
OHH2N
Ph OHNH2
PhOHH
N
Ph OHNH
PhO
ONH
Good inhib in vitro (both stereoisomers)
HN
O
O
O
O
-Bad water sol. and oral bioavail.-X-ray indicate modification of Cbz allowed
HN
Ph
NH
PhO
ONH
HN
O
O
O
O
NN
OH
Somewhat increased bioavail. without OH
Increase water sol.
Metabolic oxidation
Mw >500!
-Somewhat lower Mw-Thiazol instead of pyridine
-FDA March 1996, now many resistant strains
-Ritonavir inhib. 3A4 isozyme of CypP450Used in combi. with other protease inhib. to suppress their metab.
Saquinavir (green) bound to HIV-1 Protease
HN N
H
OH
PhO
O
N
H
H
ONH2
NHO
SaquinavirFortovase®
IndinavirCrixivan®
NelfinavirViracept®
AmprenavirAgenerase®
LopinavirKaletra®
OHN N
HN
OH
PhO
PhONH
O
OH
O
HN
OHPh
NN
N
O NH
HN
OH
SPh
OOH
H
H
O NH
HN O
OH
PhOONS
O O