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