Dúvidas [email protected] Arquivo Farmacologia dos antivirais.ppt Site Dúvidas [email protected] Arquivo Farmacologia dos antivirais.ppt

Dúvidas

[email protected]

Arquivo

Farmacologia dos antivirais.pptFarmacologia dos antivirais.ppt

Site

www.gdenucci.com

Dúvidas

[email protected]

Arquivo

Farmacologia dos antivirais.pptFarmacologia dos antivirais.ppt

Site

www.gdenucci.com

Datas importantes em AIDSDatas importantes em AIDS

• 05/06/1981 - 5 casos de P carinii pneumonia em gays masculinos

• 16/07/1982 - 3 casos em hemofílicos• 24/09/1982 - AIDS • 10/1982 - 5 casos em mulheres• 10/12/1982 - transfusão em crianças• 17/12/1982 - transmissão vertical (4 casos)

• 05/06/1981 - 5 casos de P carinii pneumonia em gays masculinos

• 16/07/1982 - 3 casos em hemofílicos• 24/09/1982 - AIDS • 10/1982 - 5 casos em mulheres• 10/12/1982 - transfusão em crianças• 17/12/1982 - transmissão vertical (4 casos)

Datas importantes em AIDSDatas importantes em AIDS07/01/1983

Transmissão heterossexual em parceiras de usuários de drogas

20/05/1983

Vírus isolado de um paciente com AIDS

03/1985

Testes comerciais para detectar HIV

03/1987

AZT (zidovudina) comercialmente disponível

Datas importantes AIDS - IIDatas importantes AIDS - II

1991 - didanosina e zalcitabina

1993 - maior causa de morte 25-44 anos (EUA)

1995 – saquinavir (inibidor de protease)

1996 - queda de mortalidade nos EUA

2006 – expectativa de vida igual à pessoa sadia

1991 - didanosina e zalcitabina

1993 - maior causa de morte 25-44 anos (EUA)

1995 – saquinavir (inibidor de protease)

1996 - queda de mortalidade nos EUA

2006 – expectativa de vida igual à pessoa sadia

Incidência e morte por HIV nos EUAIncidência e morte por HIV nos EUAIncidência e morte por HIV nos EUAIncidência e morte por HIV nos EUA

YearYearYearYear

No.

of

Cas

es o

r D

eath

sN

o. o

f C

ases

or

Dea

ths

No.

of

Cas

es o

r D

eath

sN

o. o

f C

ases

or

Dea

ths

Incidence of AIDSIncidence of AIDSIncidence of AIDSIncidence of AIDS

AIDS-related deathsAIDS-related deathsAIDS-related deathsAIDS-related deaths

RetrovírusRetrovírus

Material genético - RNA

Necessita integração do genoma viral no

DNA do hospedeiro (integrase) - provirus

RetroviridaeRetroviridae

Oncovirinae - oncongênicos e não

oncogênicos

Spumavirinae – infeções persistentes na

ausência de doença clínica

Lentivirinae – doença do sistema

imunológica de progressão lenta

LentivirusesLentiviruses

Primatas - HIV-1 e SIV

Não-primatasNão-primatas - FIV, vírus da anemia em

infecções equinas, BIV

Primatas - HIV-1 e SIV

Não-primatasNão-primatas - FIV, vírus da anemia em

infecções equinas, BIV

Accessorygenes

Accessorygenes

Accessorygenes

Accessorygenes

Accessorygenes

Accessorygenes

Accessorygenes

Accessorygenes

U3 R U5U3 R U5 gaggag propro polpol envenv U3 R U5U3 R U5

MA CA NC PR RT IN SU TMMA CA NC PR RT IN SU TM

LTRLTR LTRLTR~ 7-12 kb~ 7-12 kb

Retrovirus genome structureRetrovirus genome structureRetrovirus genome structureRetrovirus genome structure

Host genomic DNAHost genomic DNA

Gifford and Tristem - Virus Genes: 26:3, 291 – 315, 2003Gifford and Tristem - Virus Genes: 26:3, 291 – 315, 2003

a) Integrated DNA provirusa) Integrated DNA provirus

Retrovirus genome structureRetrovirus genome structureRetrovirus genome structureRetrovirus genome structure

b) Viral genomic RNAb) Viral genomic RNA

PBSPBS

R U5R U5 gag pro pol env gag pro pol env

PPTPPT

U3 RU3 R

LeaderRegionLeaderRegion

5’ CAP5’ CAP AAA 3’AAA 3’

Gifford and Tristem - Virus Genes: 26:3, 291 – 315, 2003Gifford and Tristem - Virus Genes: 26:3, 291 – 315, 2003

Lentiviruses Structural GenesLentiviruses Structural Genes

gag - proteínas estruturais e enzimas para

a replicação viral

pol - proteínas estruturais e enzimas para a

replicação viral

env – glicoproteínas do envelope viral

gaggag

MA – montagem do vírion

capsídeo – core hidrofóbico do vírion

nucleocapsídeo – recobre o RNA viral

Vários polipeptídeos - p1, p2 e p6

polpol

protease – lisa as proteínas expressas pelo

gag e gag-pol.

transcriptase reversa

integrase

TranscriptaseTranscriptase Reversa Reversa

DNA-polimerase dependente de RNA

RNAase H

DNA-polimerase dependente de DNA

envenv

Proteínas de binding e entrada na célula

glicoproteína gp 160 - gp120(SU) e

gp41(TM)

gp120 - binding; gp41 - fusão

Genes regulatórios do Genes regulatórios do HIVHIV

tat, rev

Primeiras proteínas a serem sintetizadas

após integração viral

tat and rev aumentação a produção do

mRNA viral

Genes acessórios do Genes acessórios do HIVHIV

Vif, vpr, vpu e nef

vif - virion infectivity factor

vpr - viral protein R - apoptosis

nef – essencialp para a virulência do HIV

- inibe a expressão do MHCI

Vif, vpr, vpu e nef

vif - virion infectivity factor

vpr - viral protein R - apoptosis

nef – essencialp para a virulência do HIV

- inibe a expressão do MHCI

Sidney cohort (mutação no nef)Sidney cohort (mutação no nef)

Length of Infection (yr)Length of Infection (yr)

CD

4 C

ells

(p

er m

mC

D4

Cel

ls (

per

mm

33 ))

Structure of the human immunodeficiency virus.

Ciclo do HIVCiclo do HIV

Ligação (binding) e entradaLigação (binding) e entrada

Glicoproteína do envelope viral – tropismo

viral

HIV-1 - CD4 & CCR5 ou CXCR4

Glicoproteína do envelope viral – tropismo

viral

HIV-1 - CD4 & CCR5 ou CXCR4

EnfuvirtideEnfuvirtide

Nature Reviews, may 2003, volume 2 No 5Nature Reviews, may 2003, volume 2 No 5

Enfuvirtide

• 36 aminoácidos

• Liga-se a glicoproteína 41 viral

• 90 mg 2x/dia

• T1/2 – 3.5-4 h

Budding of newBudding of newvirus particlesvirus particles

Budding of newBudding of newvirus particlesvirus particles

Anionic polymersAnionic polymersAnionic polymersAnionic polymers

Mode of action of enfuvirtide



Proteolytic processingProteolytic processingof viral proteinsof viral proteins

Proteolytic processingProteolytic processingof viral proteinsof viral proteins

Transcription andTranscription andtranslationtranslation

Transcription andTranscription andtranslationtranslation

Integration of viral DNAIntegration of viral DNAInto host genomeInto host genome

Integration of viral DNAIntegration of viral DNAInto host genomeInto host genome

Reverse transcriptionReverse transcriptionReverse transcriptionReverse transcription

Virus entryVirus entryVirus entryVirus entry

Virus attachment toVirus attachment tohost cellhost cell

Virus attachment toVirus attachment tohost cellhost cell

CD4 inhibitors chemokineCD4 inhibitors chemokineReceptor inhibitorsReceptor inhibitorsEnfuvirtideEnfuvirtide

CD4 inhibitors chemokineCD4 inhibitors chemokineReceptor inhibitorsReceptor inhibitorsEnfuvirtideEnfuvirtide

NRTIs, NNRTIsNRTIs, NNRTIsNRTIs, NNRTIsNRTIs, NNRTIs

Integretor inhibitorIntegretor inhibitorIntegretor inhibitorIntegretor inhibitor

PIsPIsPIsPIs

a)a)

CD4+targetcell

CD4+targetcell

gp120gp120 gp120gp120

VirusVirus

gp41gp41

EnfuvirtideEnfuvirtide

FusionFusion No FusionNo Fusion

Pre-hairpin intermediate Pre-hairpin intermediate




CD4CD4

b)b)

Maraviroc - Drugs 2007; 67 (15): 2277-2288

Maraviroc

Features and properties of maraviroc (CelsentriR; Selzentry®)

Maraviroc - Drugs 2007; 67 (15): 2277-2288

Maraviroc


Maraviroc - Drugs 2007; 67 (15): 2277-2288

Maraviroc


Maraviroc - Drugs 2007; 67 (15): 2277-2288

Maraviroc


Maraviroc - Drugs 2007; 67 (15): 2277-2288

Maraviroc


Maraviroc - Drugs 2007; 67 (15): 2277-2288

Ciclo do HIV e sítios para tratamentoCiclo do HIV e sítios para tratamento

Transcrição reversaTranscrição reversa

DNA linear duplo

Enzima com baixa fidelidade – genoma viral

altamente variável

DNA linear duplo

Enzima com baixa fidelidade – genoma viral

altamente variável

Bases, nucleosídeos e nucleotídeos

http://en.wikipedia.org/wiki/Image:Thymine_chemical_structure.png

Wikipedia, the free encyclopedia – DNA - Properties

The chemical structure of DNA. Hydrogen bonds are shown as dotted lines.

http://upload.wikimedia.org/wikipedia/commons/e/e4/DNA_chemical_structure.svg

AZT e TimidinaAZT e Timidina

Inibidores nucleosídicos/nucleotídicos Inibidores nucleosídicos/nucleotídicos da transcriptase reversa (NRTI)da transcriptase reversa (NRTI)

Todos os nucleosídeos/nucleotídeos devem ser fosforilados

(forma de tri-fosfato)

Os nucleotídeos tipo PMEA e PMPA já são equipados com

1 P (necessitam apenas duas fosforilações) – não necessitam

da timidina kinase e são mais potentes que as bases não

fosforiladas

Todos os nucleosídeos/nucleotídeos devem ser fosforilados

(forma de tri-fosfato)

Os nucleotídeos tipo PMEA e PMPA já são equipados com

1 P (necessitam apenas duas fosforilações) – não necessitam

da timidina kinase e são mais potentes que as bases não

fosforiladas

bis (POM) - PMEAAdefovir dipivoxyl

Inibidores Inibidores NÃO NÃO nucleosídicos/nucleotídicos nucleosídicos/nucleotídicos da transcriptase reversa (NNRTI)da transcriptase reversa (NNRTI)

Interação alostérica, mas não no sítio catalítico

Nevirapina, devalvirdina e efavirenz em uso clínico

Emivirina em fase III.

Induzem resistência rapidamente (evitada com NRTI)

Interação alostérica, mas não no sítio catalítico

Nevirapina, devalvirdina e efavirenz em uso clínico

Emivirina em fase III.

Induzem resistência rapidamente (evitada com NRTI)

Ciclo do HIV e sítios para tratamentoCiclo do HIV e sítios para tratamento

IntegraIntegraçãoçãoIntegraIntegraçãoção

Lisa os terminais 5’ and 3’

cataliza integração no genoma do hospedeiro

essencial para expressão gênica do retrovírus

alvo terapêutico específico

turnover baixo da enzima

Raltegravir

Lisa os terminais 5’ and 3’

cataliza integração no genoma do hospedeiro

essencial para expressão gênica do retrovírus

alvo terapêutico específico

turnover baixo da enzima

Raltegravir

Raltegravir

Raltegravir is taken orally twice daily. Doses of 200, 400, and 600 mg have been studied.At the 2007 Conference on Retroviruses and Opportunistic Infections, researchers presented Phase III data showing that 77% of patients taking the 400 mg dose of raltegravir plus other antiretroviral drugs reached HIV viral loads below 400 copies, nearly twice as many compared with a control group.

Wikipedia, the free encyclopedia - Raltegravir

http://upload.wikimedia.org/wikipedia/commons/a/ad/Raltegravir.png

http://upload.wikimedia.org/wikipedia/commons/7/72/Isentress_pilules.png

Ciclo do HIV e sítios para tratamentoCiclo do HIV e sítios para tratamentoCiclo do HIV e sítios para tratamentoCiclo do HIV e sítios para tratamento

TranscriTranscriçãoção ee síntese das proteínas viraissíntese das proteínas viraisTranscriTranscriçãoção ee síntese das proteínas viraissíntese das proteínas virais

Proteínas expressas pelo gens rev, tat and

nef

Proteínas expressas pelo gens rev, tat and

nef

Montagem do vírion e liberaçãoMontagem do vírion e liberaçãoMontagem do vírion e liberaçãoMontagem do vírion e liberação

RNA Viral e proteínas estruturais são empacotados

Poliproteínas gag e pol são clivadas pela protease viral

Protease do HIV e inibidorProtease do HIV e inibidorProtease do HIV e inibidorProtease do HIV e inibidor

AAAA

Protease do HIV e inibidorProtease do HIV e inibidorProtease do HIV e inibidorProtease do HIV e inibidor

BBBB

The crystal structure of the wild-type HIV-1 protease

Protease inhibitor resistance in HIV-infected patients: Molecular and clinical perspectives - Antiviral Research 76 (2007) 203–221

Protease do HIVProtease do HIVProtease do HIVProtease do HIV

Gag-pol - apresenta atividade aspartil protease

Protease gera 3 proteínas grandes (p24, p17 e p7) - estrutura

do vírion e empacotamento do RNA

Protease gera 3 proteínas pequenas (p6, p2 e p1) - desconhecido

proteases de mamíferos são pouco eficientes para

gag-pol viral

Gag-pol - apresenta atividade aspartil protease

Protease gera 3 proteínas grandes (p24, p17 e p7) - estrutura

do vírion e empacotamento do RNA

Protease gera 3 proteínas pequenas (p6, p2 e p1) - desconhecido

proteases de mamíferos são pouco eficientes para

gag-pol viral

IndinavirIndinavirIndinavirIndinavir

NelfinavirNelfinavirNelfinavirNelfinavir

RitonavirRitonavirRitonavirRitonavir

SaquinavirSaquinavirSaquinavirSaquinavir

H

AmprenavirAmprenavirAmprenavirAmprenavir

Inibidores Inibidores peptídicos peptídicos da Prda Protease do HIVotease do HIVInibidores Inibidores peptídicos peptídicos da Prda Protease do HIVotease do HIV

análogos sintéticos de fenilalanina-prolina ou tirosina-

prolina

indinavir, nelfinavir, ritonavir, saquinavir, amprenavir

previne novas infecções

metabolizados por P-450 (isoforma 3A4)

cuidado com indutores tipo rifampin e rifabutin

Atazanavir – potente t1/2 longo (1x/dia) – clinicamente

disponível

análogos sintéticos de fenilalanina-prolina ou tirosina-

prolina

indinavir, nelfinavir, ritonavir, saquinavir, amprenavir

previne novas infecções

metabolizados por P-450 (isoforma 3A4)

cuidado com indutores tipo rifampin e rifabutin

Atazanavir – potente t1/2 longo (1x/dia) – clinicamente

disponível

Atazanavir

Inibidores Inibidores peptídicos peptídicos da Protease do HIV da Protease do HIV Considerações farmacocinéticasConsiderações farmacocinéticas

Inibidores Inibidores peptídicos peptídicos da Protease do HIV da Protease do HIV Considerações farmacocinéticasConsiderações farmacocinéticas

Ritonavir aumenta 20-30x saquinavir (primeira passagem)

Indinavir aumenta 5x saquinavir

Rifampin e inibidores de protease (complicado)

Diminuição de etinilestradiol (nelfinavir e ritonavir)

Não afeta níveis dos nucleosídeos

Cuidado com benzodiazepínicos, antihistamínicos

Ritonavir aumenta 20-30x saquinavir (primeira passagem)

Indinavir aumenta 5x saquinavir

Rifampin e inibidores de protease (complicado)

Diminuição de etinilestradiol (nelfinavir e ritonavir)

Não afeta níveis dos nucleosídeos

Cuidado com benzodiazepínicos, antihistamínicos

Efeitos Colaterais de Inidores Efeitos Colaterais de Inidores Peptídicos Peptídicos de Proteasede ProteaseEfeitos Colaterais de Inidores Efeitos Colaterais de Inidores Peptídicos Peptídicos de Proteasede Protease

Náusea, vômito, diarréia

astenia e fatiga

nefrolitíase - indinavir (baixa hidrossolubilidade)

lipodistrofia

aumento de bilirrubina, AST, ALT, trigliceridas e

glicemia

parestesia

Náusea, vômito, diarréia

astenia e fatiga

nefrolitíase - indinavir (baixa hidrossolubilidade)

lipodistrofia

aumento de bilirrubina, AST, ALT, trigliceridas e

glicemia

parestesia

Resistência aos inibidores Resistência aos inibidores peptídicos peptídicos de proteasede proteaseResistência aos inibidores Resistência aos inibidores peptídicos peptídicos de proteasede protease

Fenilalanina por valina (p82)

Aspartato por asparigina (p30)

1/3 pode mutar sem problemas (99 aa)

monoterapia contra-indicada

aderência é fundamental

5,000-10,000 cópias/mL - 1 inibidor de protease

+ 2 inibidores de RT

Fenilalanina por valina (p82)

Aspartato por asparigina (p30)

1/3 pode mutar sem problemas (99 aa)

monoterapia contra-indicada

aderência é fundamental

5,000-10,000 cópias/mL - 1 inibidor de protease

+ 2 inibidores de RT

Inibidores Inibidores não peptídicos não peptídicos da Prda Protease do HIVotease do HIVInibidores Inibidores não peptídicos não peptídicos da Prda Protease do HIVotease do HIV

Os inibidores peptídicos desenvolvem resistência

Não peptídicos – apresentam melhor biodisponibilidade

oral

Largo espectro anti-HIV

Mozenavir (provavelmente não vai entrar no mercado) e

Tipranavir (este último já no mercado)

Os inibidores peptídicos desenvolvem resistência

Não peptídicos – apresentam melhor biodisponibilidade

oral

Largo espectro anti-HIV

Mozenavir (provavelmente não vai entrar no mercado) e

Tipranavir (este último já no mercado)

Mozenavir

TripanavirTripanavir

Tipranavir

• http://biosingularity.wordpress.com/2007/07/04/super-3d-animation-that-shows-the-mode-of-action-of-an-hiv-drug/

http://biosingularity.wordpress.com/2007/07/04/super-3d-animation-that-shows-the-mode-of-action-of-an-hiv-drug/



Morphology of PEO–PCL nanoparticles loaded with saquinavir

Polymeric Nanoparticles for Enhancing Antiretroviral Drug - Therapy - Drug Delivery, xxxx:1–9, 2008 Copyright c Informa UK, Ltd - ISSN: 1071-7544 print / 1521-0464 online

Intracellular concentrations of saquinavir as a function of dose administered(A) and time of incubation (B) to THP-1 monocyte/macrophage cells.

Tritiated [3H]-saquinavir was administered in aqueous solution: filled circles and in poly (ethylene oxide)-modified poly(epsilon-caprolactone) (PO-PCI) nanoparticles: empty circles at different doses and incubated for different duration. To evaluate the effect of incubation time,

saquinavir concentration was held constant at 50 nM (Shah and Amiji 2006)



Life cycle of HIV and site of action of antiretroviral therapy

Ten years of highly active antiretroviral therapy for HIV infection - MJA • Volume 186 Number 3 • 5 February 2007

Autoimmune disease and HIV Autoimmune disease and HIV

IHIV

IHIV

IILatency

IILatency

IIIAIDS

IIIAIDS

IVHAART

IVHAART

Stage of autoimmune responseStage of autoimmune response

AutoimmuneresponseAutoimmuneresponse

Total CD4 countTotal CD4 count

Autoimmunity Reviews 1, (2002) 329-337Autoimmunity Reviews 1, (2002) 329-337

HBV replication cycle and site of action of several anti-HBV agents. The numbered steps are discussed in the text

Antiviral treatment of chronic hepatitis B virus infections: the past, the present and the future Rev. Med. Virol. 2008; 18: 19–34. - Published online 26 October 2007 in Wiley InterScience

Hepatitis B viral antigens and antibodies detectable in the blood following acute infection.

Wikipedia, the free encyclopedia - Hepatitis B virus - Diagnosis

Hepatitis B viral antigens and antibodies detectable in the blood of a chronically infected person

Wikipedia, the free encyclopedia - Hepatitis B virus - Diagnosis

Fatores preditivos de terapia com interferon alfa em hepatite B crônica

• Sexo feminino• Infecção em adulto• ALT elevada• Níveis baixos de DNA séricos para HBV• Alto grau de neuroinflamação hepática• Ausência de infecção por hepatite D ou HIV

Tratamento da Hepatite B

• Alfa-interferon (com PEG)

• Lamivudina – inibidor HBV DNA polimerase

• Adefovir dipivoxil – inibidor DNA polimerase

• Entecavir – análogo da guanosina – inibidor de DNA polimerase

• Emtricitabine – análogo da lamivudina

• Telbivudine – inibidor da HBV DNA polimerase

• Clevudine – inibidor da HBV DNA polimerase

Comparison of oral agents in treatment-naive patients who have HBeAg-positive chronic hepatitis B*

Oral Antivirals for Chronic Hepatitis B - Clin Liver Dis 11 (2007) 851–868

Comparison of oral agents in treatment-naive patients with HBeAg-negative chronic hepatitis B*

Oral Antivirals for Chronic Hepatitis B - Clin Liver Dis 11 (2007) 851–868

Indication for observing and treating HBV

Antiviral therapy and resistance with hepatitis B virus Infection - World J Gastroenterol 2007 January 7; 13(1): 125-140

Antiviral therapy and resistance with hepatitis B virus Infection - World J Gastroenterol 2007 January 7; 13(1): 125-140

Treatment options for chronic hepatitis B and their profile

Drugs used to treat HBV in patients co-infected with HIV

Evaluation and Treatment of the Patient Coinfected With Hepatitis B and HIV Current HIV/AIDS Reports 2008, 5:103–111

Characteristics of the principal human IFN genes

Interferon-based therapy of hepatitis C - Advanced Drug Delivery Reviews 59 (2007) 1222–1241

Characteristics of the principal human IFN genes (cont.)


Characteristics of the principal human IFN genes (cont.)


Alfa-interferon com PEG

• 2a: ligado a 40KD PEG, t1/2=100 hrs

• 2b: ligado a 12KD PEG

Tratamento da Hepatite C

• Interferon alfa com PEG + Ribavirin

• Inibidores de NS3-4a Protease

• Inibidores de NS5B polimerase

Pharmacological parameters of pegylated IFN–α molecules used in the treatment of chronic hepatitis C


Current guidelines for chronic hepatitis C treatment with pegylated IFN–α and ribavirin, according to the HCV genotype

HCV genotype 1



HCV genotypes 2 and 3



HCV genotypes 4, 5 and 6


Pathway for processing for RNA interference (RNAi) activity.

Cellular long double-strand RNA (dsRNA) and premicroRNA (miRNA) are cleaved by Dicer to short interfering RNA (siRNA) or miRNA shorter than 30 bp in length. These pieces bind to RNA-inducted silencing complex (RISC); one strand is separated off while the remaining strands stay bound to RISC. This RISC strand binds to messenger RNA (mRNA) of exact sequence (siRNA) or similar sequence (miRNA) to either cause degradation of mRNA or block in translation, respectively. Introduction into the cell of precursor RNA from an exogenous source such as a viral vector containing short hairpin RNA (shRNA) constructs or siRNA alone can also feed into the RNAi pathway. shRNA is cleaved by Dicer to siRNA; siRNA bypasses Dicer. Either species then binds to RISC and continues into the RNAi pathway as described. AGO2—argonaute2.

The Potential of RNA Interference – based Therapies for Viral Infections - Current HIV/AIDS Reports 2008, 5:33–39 Current Medicine Group LLC ISSN 1548-3568

C E1 E2 NS2 NS3 NS4b NS5a NS5b

C E1 E2 NS2 NS3 NS4b NS5a NS5b

Genome

Proteins

Functions

5’-UTR 3’-UTR

Capsid protein

Envelope proteins

Metallo-protease

Serine protease*

RNA helicase

Protease cofactor

Replication and IFN-resistance

RNA polymerase*

NS4ap7

?

NS4ap7

HCV is a Flavivirus family member and has a positive-sense, ssRNA genome that serves as the basis for both genome replication and protein translation.

Emerging host cell targets for hepatitis C therapy - Drug Discovery Today Volume 12, Numbers 5/6 March 2007

Host cell

HCV

Viral targets

Antiviral response

• IFN (Jak-Stat) pathway• ISGs (PKR, etc.)• TLR pathway• Oxidative stress response• Adaptive immunity

Celular cofactors

• Cell-surface receptors• HCV RC cofactors• Nucleotide biosynthesis• Lipid biosynthesis• Host-cell glycosylation• Cellular kinases

HCV uses numerous cellular pathways and cofactors to complete its life cycle.


Pros and cons of viral versus cellular targets

Viral targets Cellular targets

√a Vira-specific

X Limited action spectrum

X Limited market

X Viral target mutation

X Limited number of target

X Requiring novel inhibitors

X Lack of specificity; side effects

√ Broad action spectrum

√ Broad market

√ Lack of cellular target mutation

√ Large number of targets

√ Existing drugs; indication switch

a √, pro; X, con


5/23

0/763/162

0/9

5/23

1/824/165

0/11

P>0.0008v Peg-IFN-α2a

Peg-IFN-α2a + lamivudine

P=0.018

25.0

20.0

15.0

10.0

5.0

0.0

Genotype dependece of HBsAg clearance

A B C D A B C D

HBsAg seroconversion occurs more frequently on HBV genotoype “A” compared to the other Genotypes.

Antiviral therapy and resistance with hepatitis B virus infection - World J Gastroenterol 2007 January 7; 13(1): 125-140

25.0

20.0

15.0

10.0

5.0

0.0Grade 1 Grade 2 Grade 3 Grade 4

Hepatitis frequency and WHO severity on chemotherapy W/W.o Lam

Lamivudine

No lamivudine

Pre-emptive lamivudine is associated with lower frequency and lower severity of hepatitis during chemotherapy. Date given in percent (%).


0

-1

-2

-3

-4

-5

-6

-7

-8End of treatment response 24 wk follow-up

Reduction of HBV viral load on Peg-interferon & lamivudine

-7.2

-4.5

-5.8

-2.4 -2.6-2

Peg + Lam

Peg

Lam

Viral load reduction at the end of treatment and at 24 wk follow-up in thedifferent treatment arms.


0 5 10 15 20 220

500

400

300

200

100

0

t (treatment)/wk

Med

ian

of

HB

V-D

NA

(p

g/m

L)

Responder n = 6Slow-responder n = 7Non-responder n = 8

Virological response pattern on famciclovir

Different response pattern on famciclovir.


Improvement on famciclovir in a patient with continuous deterioration prior to initiation of famciclovir therapy.


HBV-DNA reduction Inlfammation Fibrosis

ADV 10 mg (n = 171)

ADV 30 mg (n = 173)

Placebo (n = 167)

0

-1

-2

-3

-4

-5

Reduction in HBV-DNA, as well as histological improvement in inflammation and fi brosis according to the Knodell score after 48 wk

therapy with 10, 30 mg ADV


70

60

50

40

30

20

10

01 2

Resistence development on antivirals LAMADV (LAM-R)ETV (Lam-R)FTCADVETVLdT

Prevalence of resistance on different antivirals, up to 2 year data.


(yr)


70

60

50

40

30

20

10

01 2 3 4 5

LamADV

(yr)

Prevalence of resistance on different antivirals, up to 5 year data.

Potential mechanisms (A–E) for HIV-1 transmission across the mucosal epithelium

Microbicide drug candidates to prevent HIV infection - Lancet 2007; 369: 787–97

Target sites and mechanisms of microbicides


● Potent activity against most HIV strains

● Preferably broad activity against other sexually transmitted pathogens

● Direct virucidal activity

● Preservation of microbicidal activity in the presence of seminal fluid

● Effective against both cell-free and cell-associated HIV

● No effect on the structural integrity of vaginal, cervical, or rectal mucosal epithelium

● No effect on vaginal commensal flora, especially lactobacilli

● Preferentially contraceptive properties

● Resistant to acidic, vaginal pH or enforcing an acidic pH

● Stable at higher, tropical temperatures

● Odourless, colourless, and tasteless

● Compatibility with latex

● Easy to use

● Low cost and readily accessible

● Acceptable to all sexual partners

Properties of an ideal anti-HIV microbicide


Top and side views of the three important conformations of HIV-1 protease

(a) The ‘closed’ form is observed in crystal structures with ligands bound.

(b) The flaps of the free protease assume a ‘semi-open’ conformation in crystal structures (PDB 1HHP is shown). The three top views (a–c) highlight the change in flap handedness between closed and semi-open structures. Proposed allosteric inhibition sites are labeled as (i) and (ii).

(c) The fully ‘open’ form in which the active site becomes accessible to substrate or inhibitors was not observed in crystal structures but was implied from NMR experiments. The structure shown is from molecular dynamics simulations [

Targeting structural flexibility in HIV-1 protease inhibitor binding - Drug Discovery Today Volume 12, Numbers 3/4 February 2007

Snapshots from molecular dynamics simulations of inhibitor-bound and free protease, and from simulations following the manual docking of the inhibitor

into the binding site.

The ‘closed’ conformation (a) is represented by an ensemble of closed structures with high similarity (f). By contrast, the ‘semi-open’

conformation (b) represents a much more flexible ensemble (g) with larger fluctuations of the flaps. These eventually lead to full

opening of flaps (c,d); the ‘open’ form is transient and returns to the semi-open conformation (e). When the inhibitor is manually

placed into a binding site (h), it induces na asymmetric flap closure with initial closing of one of the flaps (i), finally converting to the

fully closed form (j) with flaps pulled into the binding site and flap handedness appropriate for the closed state.


‘Open’

Add ligand

No ligand‘Closed’

Bound protease‘Semi-open’ Free proteaseRemove ligand

Schematic representation of simulated transitions between the three protease forms.

The ‘closed’ flap conformation converts to the ‘semiopen’ one upon removal of ligand. Ligand induces the closure of the ‘open’ form. Free protease exists primarily in the semi-open form but transiently changes to the fully open form and, occasionally, even to the closed form that is only weakly populated in the absence of a ligand.


The mechanisms whereby a CD8+ T cell kills a virus-infected host cell

Pharmacology – fifth edition – fig. 46.2

Schematic diagram of infection of CD4+ T cell by

na HIV virion with the sites of action of the two main classes of drug and

sites for possible new drugs

Pharmacology – fifth edition – fig. 46.4

Schematic diagram of replication of a DNA virus (e.g., herpes simplex) in a host cell with the probable sites of action of antiviral agents

Foy

es P

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iple

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icin

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y –

Fif

th e

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fig

39.

1

Antiviral Agents Interfering with Cellular Penetration and Early Replication

Generic Name Spectrum of Activity

Amantadine Influenza A

Rimantadine Influenza A

Interferon Interferon α-2a Unlabeled use:

Chronic hepatitis, CMV, HSV, Pappillomaviruses, Rhinovirses, others

Interferon α-2b Chronic hepatitis B and C, Unlabeled: many virus infections

γ-Interferon

Zanamivir Influenza A; Influenza B

Oseltamivir Influenza A; Influenza B

Foy

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Fif

th e

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tab

39.2

HIV Reverse Transcriptase (RT) Inhibitors

Generic Name Trade name

Nucleosides Reverse Transcriptase Inhibitors (NRTI)

Zidovudine Ritrovir

Didanosine Videx

(Dideoxyadenosine)

Zalcitabine Hivid

Stavudine Zerit

Lamivudine Epivir

Epivir HBV

Abacavir Ziagen

Nonnucleosides Reverse Transcriptase Inhibitors (NNRTI)

Nevirapine Viramune

Delavirdine Rescriptor

Efavirenz Sustiva

Foy

es P

rinc

iple

s of

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icin

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Fif

th e

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tab

39.2

HIV Protease inhibitors

Generic Name Trade name

Saquinavir Invirase

Fortovase

Ritonavir Norvir

Indinavir Crixivan

Nelfinavir Viracept

Amprenavir Agenerase

Lopinavir/ Kaletra

Ritonavir

Foyes Principles of Medicinal Chemestry – Fifth edition – tab 39.2

H3C-C-OCH2

H2N

O

N N

N N

O

O

C-CH3

HOCH2

H2N

HN N

N N

OH

O

Famciclovir Penciclovir

Foyes Principles of Medicinal Chemestry – Fifth edition – pag 964

Type I IFN production and signaling pathways.


The life cycle of HBV in the cell. Viral entry, formation of cccDNA, transcription and translation of viral proteins, formation of nucleocapsid and envelopment, and secretion processes are depicted

Interaction and Assembly of HBV Structural Proteins: Novel Target Sites of Anti- HBV Agents - Infectious Disorders - Drug Targets 2007, 7, 251-256

The structure of core proteins.


Structures of chemical compounds that inhibit the interaction between core proteins or misdirect the assembly of capsid


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