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QUIMIOTERAPIA ANTI VIRAL

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					Anti-Viral Chemotherapy
Bacteria
• Many antibiotics
• Highly selective

Viruses
• Use host cell metabolism • Selectivity difficult • Toxicity
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Anti-Viral Chemotherapy
Key is selectivity
Other problems

• Toxicity
• Rapid excretion • Rapid metabolism • Poor absorption
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Anti-Viral Chemotherapy
Ideal Drug
• Water soluble

• Chemically and metabolically stable
• Easily absorbed (apolar)

NOT
•Toxic • Carcinogenic • Allergenic • Mutagenic • Teratogenic
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Anti-Viral Chemotherapy
Therapeutic index (T.I.)

Minimum dose toxic to cell Minimum dose toxic to virus Effective drug: T.I. = 100-1000 at least
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Anti-Viral Chemotherapy
Another consideration:
Disease severity Rhinovirus v. Symptomatic rabies or Lassa fever

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Anti-Viral Chemotherapy
At present continuing search for anti-virals versus Reasons forno drug completely suppresses viral replication (with possible exception of anti-HIV protease inhibitors) vaccines: • For many established diseases there is still no effective vaccine • Rapid mutation (retroviruses) • Or there are problems with the current vaccine • Reassortment (influenza) • New and emerging diseases - no vaccine available

• Vaccine development takes many years
• Disease that involve immunosuppression (AIDS, cancer, transplantation)
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Anti-Viral Chemotherapy
A successful drug must interfere with:

• A specific viral function e.g. enzyme necessary for viral life cycle
• A cellular function that the virus needs in order to replicate
If interfere with cellular function either: • It must be crucial to virus but not the cell or • Only the virus-infected cell must be killed (activation of drug in the infected cell only?)
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Anti-Viral Chemotherapy
Viral enzymes
Nucleic acid polymerases • DNA-dependent DNA polymerase - DNA viruses

• RNA-dependent RNA polymerase - RNA viruses
• RNA dependent DNA polymerase (RT) - Retroviruses • Protease (retrovirus) • Integrase (retrovirus) • Neuraminidase (orthomyxovirus)
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Anti-Viral Chemotherapy
1962 Idoxuridine • Pyrimidine analog • Toxic • Topical - Epithelial herpetic keratitis (cornea) 1983 Acyclovir • Purine analog • Sugar modification • Chain terminator

• Anti-herpes
• Selective to virus-infected cells 1990‟s Protease inhibitors
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Binding

Reverse transcription

Fusion

Integration Transcription Splicing
RNA export Genomic RNA
mRNA

Endocytosis
Nuclear localization

Uncoating

Lysosome Maturation
Modification
Translation
10 Assembly

Budding

Anti-Viral Chemotherapy
Binding to surface receptor
• At present no effective drugs in this class • Soluble CD4 - May make HIV more infective as results in chemokine receptor being the only necessary receptor

CD4-Ig2 (PRO542) - A more stable version of soluble CD4 is a tetrameric fusion protein of immunoglobulin G and CD4. It can reduce levels of virus in vivo AMD3100 - appears to bind to CXCR4 (fusin)
RFI-641 (biphenyl triazine) active against RSV fusion
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Anti-Viral Chemotherapy
Membrane Fusion

T-20 FUZEON (enfuvirtide)
Peptides derived from gp41 can inhibit infection

Probably block interaction of gp41 with cell membrane proteins during fusion
T-20: In clinical trials, a nearly two log reduction in plasma HIV levels achieved T-1249 Next generation: Different site from T-20
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Anti-Viral Chemotherapy
Membrane Fusion
Endosome low pH often necessary for membrane fusion • Lysosomotropic agents

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Anti-Viral Chemotherapy
Amantadine: 1966 Rimantadine: 1993
Only effective against ‘flu A (200mg/day)
• Marginally effective therapeutically
• Prophylaxis: Reduce flu by 90% Amantadine Rimantadine

Since disease usually mild and avoidable not used much here Good alternative to vaccine for: Lysosomotropic drugs? • Elderly
• Immunocompromized
• Allergic • Where causative strain not the vaccine strain Affects M2 Golgi ion channel involved in activation of virus before release from cell
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Anti-Viral Chemotherapy
Uncoating of core of membrane and nonmembrane viruses
• Uncoating of picornavirus e.g. polio, echo, rhino

• Stabilize coated virus?

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N O

Anti-Viral Chemotherapy
O

CH3
WIN 71711 (Disoxaril) O N

• Stabilizes picornaviruses - coated virus remains in cytoplasm • 3-methylisoxazole group inserts in capsid VP1 and covers ion channel

3-methyl isoxazole group

Old formulation workedPleconaril Similar mechanism: poorly (oral) New formulation (nasal spray) Good bioavailability – readily absorbed Marketed (2004) by Schering-Plough Crosses blood-brain barrier

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Anti-Viral Chemotherapy

VP1

VP1

Human rhinovirus with WIN drug – embeds in VP1

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Anti-Viral Chemotherapy
Nucleic Acid Synthesis
Polymerases are often virally encoded

Other enzymes in nucleic acid synthesis e.g. THYMIDINE KINASE in Herpes Simplex
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Anti-Viral Chemotherapy
Thymidine Kinase
Viral or cellular thymidine kinase adds first phosphate

Deoxy-thymidine

Deoxy-thymidine triphosphate

Cellular kinases add two more phosphates to form TTP

PO4 PO4 PO4

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Anti-Viral Chemotherapy
Why does Herpes simplex code for its own thymidine kinase? TK- virus cannot grow in neural cells because they are not proliferating (not making DNA) Although purine/pyrimidines are present, levels of phosphorylated nucleosides are low Allows virus to grow in cells that are not making DNA

“Thymidine kinase” is a misnomer

Deoxynucleoside kinase

NON-SPECIFIC 20

Anti-Viral Chemotherapy
Herpes thymidine kinase will phosphorylate any deoxynucleoside including drugs – as a result of its necessary non-specificity Nucleoside analog may be given in non-phosphorylated form • Gets drugs across membrane • Allows selectivity as only infected cell has enzyme to phosphorylate the drug Cellular TK (where expressed) does not phosphorylate (activate) the drug

ACG P P P 21

Anti-Viral Chemotherapy
Need for activation restricts drug to:

• Viruses such as HSV that code for own thymidine kinase
• Virus such as cytomegalovirus and Epstein-Barr virus that induce cells to overproduce their own thymidine kinase

• In either case it is the VIRUS-INFECTED cell that

activates the drug
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Anti-Viral Chemotherapy
Thymidine kinase activates drug but phosphorylated drug inhibits the polymerase

Nucleotide analogs
Sugar modifications Base modifications

Selectivity
• Viral thymidine kinase better activator

• Cellular enzyme may not be present in non-proliferating cells
• Activated drug is more active against viral DNA polymerase that 23 against cell polymerase

Anti-Viral Chemotherapy
Guanine analogs
Acyclovir = acycloguanosine = Zovirax
Ganciclovir = Cytovene

• Activated by viral TK
Acyclovir Ganciclovir • Activated ACV is better (10x) inhibitor of viral DNA polymerase than inhibitor of cell DNA polymerase
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Excellent anti-herpes drug

Anti-Viral Chemotherapy
Acyclovir:

• Chain terminator
Good anti-herpes drug

P

P

P

P

25 Normal DNA synthesis

Anti-Viral Chemotherapy
Acyclovir:
• Chain terminator
P P

Termination

Selective:
• Virus phosphorylates drug • Polymerase more sensitive ACG
P-P-P

P

P

Also inhibits:
• Epstein Barr • Cytomegalovirus

P

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Anti-Viral Chemotherapy
Acyclovir very effective against: • Herpes simplex keratitis (topical)

• Latent HSV (iv)
• Fever blisters – Herpes labialis (topical) • Genital herpes (topical, oral, iv)
Resistant mutants in thymidine kinase or DNA polymerase
Appears not to be teratogenic or carcinogenic Ganciclovir very effective against cytomegalovirus – viral DNA polymerase is very sensitive to drug activated by cell TK
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Anti-Viral Chemotherapy
Adenine arabinoside (Ara-A)
Problems : Severe side effects • Resistant mutants (altered polymerase) Competitive inhibitor of virus DNA polymerase which is much more sensitive than host polymerase • Chromosome breaks (mutagenic) • Tumorigenic in rats • Teratogenic in rabbits

• Insoluble
Use: topical applications in ocular herpes simplex
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Anti-Viral Chemotherapy
Adenine arabinoside
• HSV encephalitis
• Neonatal herpes • Disseminated herpes zoster

• Hepatitis B

Poor in vivo efficacy: DEAMINATION
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Anti-Viral Chemotherapy
Other sugar modifications:

AZT azidothymidine

DDI dideoxyinosine

DDC dideoxycytidine
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Anti-Viral Chemotherapy

Base change analogs

Altered base pairing

Trifluorouridine Viroptic anti-HSV

Mutant DNA

Idoxuridine
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Resistant mutants

Anti-Viral Chemotherapy
Fluoroiodo aracytosine has both a base and a sugar alteration

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Prodrugs e.g. Famciclovir
Penciclovir: Available as topical cream

P

P

P

Taken orally

Converted by patient’s metabolism

HSV thymidine kinase Host kinase

Glaxo-SmithKlein

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Anti-Viral Chemotherapy
Non-nucleoside Non-competitive RT inhibitors
Combination therapy with AZT

Resistance mutations will be at different sites

The most potent and selective RT inhibitors Nanomolar range Minimal toxicity (T.I. 10,000-100,000) Synergistic with nucleoside analogs (AZT) Good bio-availability Resistant mutants - little use in monotherapy
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Anti-Viral Chemotherapy

DuPont

Nevirapine Sustiva
(S) -6- chloro-4-(cyclopropylethynyl)1,4-dihydro-4-(trifluoromethyl)-2H-3, 1benzoxazin-2-one. 35

Anti-Viral Chemotherapy
Nevirapine: Approved for AIDS patients Good blocker of mother to child transmission peri-natal - breast feeding • Single dose at delivery reduced HIV transmission by 50%

• Single dose to baby by 72 hours
Efavirenz (Sustiva, DMP266)

In combination therapy will suppress viral load as well as HAART and may be better – Approved 36 for AIDS patients

Anti-Viral Chemotherapy
Phosphono acetic acid (PAA) Phosphono formic acid

O
HO P C

O

OH Binds pyrophosphate site of polymerase Competitive inhibitor 10 -100x greater inhibition of herpes polymerase Toxic: accumulates in bones, nephrotoxicity Rapid resistance
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Clinical trial: CMV in AIDS patients

Anti-Viral Chemotherapy
Ribavirin
• Guanosine analog

• Non-competitive inhibitor of RNA polymerase in vitro
• Little effect on ‘flu in vitro

• Often good in animals but poor in humans
• Aerosol use: respiratory syncytial virus • i.v./oral: reduces mortality in Lassa fever, Korean and Argentine hemorrhagic fever

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Anti-Viral Chemotherapy
May inhibit RNA cap formation
O HN CH3 N

May induce mutations in RNA viruses

H2N

N

N O CH2
P P

base
CH2 O

P

CH3
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Anti-Viral Chemotherapy
Ribozymes
RNA molecules that have catalytic properties among which are the specific cleavage of nucleic acids

Heptazyme
Ribozyme that cleaves hepatitis C RNA at highly conserved regions Recognizes and cuts all known types of the hepatitis C virus, thereby stopping viral replication Poor in clinic
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Anti-Viral Chemotherapy

Viral Protein synthesis: No inhibitors

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Anti-Viral Chemotherapy
Protein processing:

• Proteolysis
• Glycosylation

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Anti-Viral Chemotherapy
GAG/POL polyprotein GAG Integrase Polymerase Protease

Retrovirus --- HIV

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Anti-Viral Chemotherapy
GAG Integrase Polymerase

Protease folds and cuts itself free
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Anti-Viral Chemotherapy
GAG Integrase Polymerase

Protease cuts at a site between the integrase and polymerase
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Anti-Viral Chemotherapy
GAG Integrase

polymerase

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Anti-Viral Chemotherapy
Saquinavir

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Anti-Viral Chemotherapy
HIV aspartyl protease inhibitors
Saquinavir: In HAART Viremia

CD4+ cells
Indinavir+AZT+3TC Ritonavir: In HAART AIDS deaths 58%

Indinavir Nelfinavir
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Anti-Viral Chemotherapy
Indinavir (Merke)
INDINAVIR + AZT + 3TC (HAART) No detectable HIV by PCR

Before: 20,000 - 11,000,000 RNA copies /ml

After: < 200-400 copies
Lasts several years 49 No replication No resistance

Anti-Viral Chemotherapy
Influenza
Requires neuraminidase to escape from cell Requires neuraminidase to penetrate mucus

Zanamivir - RELENZA (fall 1997)
Neuraminidase inhibitor Active against Influenza A and Influenza B
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Relenza

Tamiflu (oseltamivir)

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Anti-Viral Chemotherapy
After neuraminidase inhibition, „flu hemagglutinin binds to sialic acid on other virus particles: virus clumps

OR virus sticks to mucous in respiratory tract
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Neuraminidase of virus removes sialic acid from cell surface thereby releasing virus

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Virus hemagglutinin sticks new virus particle to sialic acid on cell surface Virus cannot escape from infected cell after neuraminidase inhibition
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Anti-Viral Chemotherapy
Zanamivir - Relenza

Neuraminidase inhibitor
Nasal spray

Shortens symptoms by a few days
Tamiflu: Oral neuraminidase inhibitor

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Anti-Viral Chemotherapy
NEURAMINDIASE INHIBITORS
TREATMENT
• Oseltamivir is approved for treatment of persons aged >1 year

• Zanamivir is approved for treatment of persons aged >7 years
PROPHYLAXIS Oseltamivir and zanamivir can be used for chemoprophylaxis of influenza • Oseltamivir is licensed for use in persons aged >1 year • Zanamivir is licensed for use in persons aged >5 years

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Anti-Viral Chemotherapy
ADAMANTANES • Among influenza virusRapid emergence to amantadine andinfected participants in 10 rimantadine because of M2 point mutation clinical trials, the risk for pneumonia among those participants receiving NEURAMINIDASE INHIBITORS oseltamivir was • Development of viral resistance to zanamivir and oseltamivir during treatment has been identified approximately 50% lower than among those persons • No transmission of neuraminidase inhibitor-resistant viruses receiving a placebo in humans has been documented to date • Data are limited concerning the effectiveness of zanamivir and oseltamivir for treatment of influenza among persons at high risk for serious complications of influenza

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