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Dúvidas
denucci@gdenucci.com
Arquivo
Farmacologia dos antivirais.pptFarmacologia dos antivirais.ppt
Site
www.gdenucci.com
Dúvidas
denucci@gdenucci.com
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
Mode of action of enfuvirtide
Nature Reviews, may 2003, volume 2 No 5Nature Reviews, may 2003, volume 2 No 5
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
Mode of action of enfuvirtide
Mode of action of enfuvirtide
Nature Reviews, may 2003, volume 2 No 5Nature Reviews, may 2003, volume 2 No 5
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
Features and properties of maraviroc (CelsentriR; Selzentry®)
Maraviroc - Drugs 2007; 67 (15): 2277-2288
Maraviroc
Features and properties of maraviroc (CelsentriR; Selzentry®)
Maraviroc - Drugs 2007; 67 (15): 2277-2288
Maraviroc
Features and properties of maraviroc (CelsentriR; Selzentry®)
Maraviroc - Drugs 2007; 67 (15): 2277-2288
Maraviroc
Features and properties of maraviroc (CelsentriR; Selzentry®)
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
Wikipedia, the free encyclopedia – DNA - Properties
The chemical structure of DNA. Hydrogen bonds are shown as dotted lines.
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
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/
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)
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
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
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.)
Interferon-based therapy of hepatitis C - Advanced Drug Delivery Reviews 59 (2007) 1222–1241
Characteristics of the principal human IFN genes (cont.)
Interferon-based therapy of hepatitis C - Advanced Drug Delivery Reviews 59 (2007) 1222–1241
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
Interferon-based therapy of hepatitis C - Advanced Drug Delivery Reviews 59 (2007) 1222–1241
Current guidelines for chronic hepatitis C treatment with pegylated IFN–α and ribavirin, according to the HCV genotype
HCV genotype 1
Interferon-based therapy of hepatitis C - Advanced Drug Delivery Reviews 59 (2007) 1222–1241
Current guidelines for chronic hepatitis C treatment with pegylated IFN–α and ribavirin, according to the HCV genotype
HCV genotypes 2 and 3
Interferon-based therapy of hepatitis C - Advanced Drug Delivery Reviews 59 (2007) 1222–1241
Current guidelines for chronic hepatitis C treatment with pegylated IFN–α and ribavirin, according to the HCV genotype
HCV genotypes 4, 5 and 6
Interferon-based therapy of hepatitis C - Advanced Drug Delivery Reviews 59 (2007) 1222–1241
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.
Emerging host cell targets for hepatitis C therapy - Drug Discovery Today Volume 12, Numbers 5/6 March 2007
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
Emerging host cell targets for hepatitis C therapy - Drug Discovery Today Volume 12, Numbers 5/6 March 2007
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 (%).
Antiviral therapy and resistance with hepatitis B virus infection - World J Gastroenterol 2007 January 7; 13(1): 125-140
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.
Antiviral therapy and resistance with hepatitis B virus infection - World J Gastroenterol 2007 January 7; 13(1): 125-140
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.
Antiviral therapy and resistance with hepatitis B virus infection - World J Gastroenterol 2007 January 7; 13(1): 125-140
Improvement on famciclovir in a patient with continuous deterioration prior to initiation of famciclovir therapy.
Antiviral therapy and resistance with hepatitis B virus infection - World J Gastroenterol 2007 January 7; 13(1): 125-140
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
Antiviral therapy and resistance with hepatitis B virus infection - World J Gastroenterol 2007 January 7; 13(1): 125-140
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.
Antiviral therapy and resistance with hepatitis B virus infection - World J Gastroenterol 2007 January 7; 13(1): 125-140
(yr)
Antiviral therapy and resistance with hepatitis B virus infection - World J Gastroenterol 2007 January 7; 13(1): 125-140
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
Microbicide drug candidates to prevent HIV infection - Lancet 2007; 369: 787–97
● 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
Microbicide drug candidates to prevent HIV infection - Lancet 2007; 369: 787–97
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.
Targeting structural flexibility in HIV-1 protease inhibitor binding - Drug Discovery Today Volume 12, Numbers 3/4 February 2007
‘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.
Targeting structural flexibility in HIV-1 protease inhibitor binding - Drug Discovery Today Volume 12, Numbers 3/4 February 2007
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
rinc
iple
s of
Med
icin
al C
hem
estr
y –
Fif
th e
diti
on –
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
es P
rinc
iple
s of
Med
icin
al C
hem
estr
y –
Fif
th e
diti
on –
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
Med
icin
al C
hem
estr
y –
Fif
th e
diti
on –
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.
Interferon-based therapy of hepatitis C - Advanced Drug Delivery Reviews 59 (2007) 1222–1241
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.
Interaction and Assembly of HBV Structural Proteins: Novel Target Sites of Anti- HBV Agents - Infectious Disorders - Drug Targets 2007, 7, 251-256
Structures of chemical compounds that inhibit the interaction between core proteins or misdirect the assembly of capsid
Interaction and Assembly of HBV Structural Proteins: Novel Target Sites of Anti- HBV Agents - Infectious Disorders - Drug Targets 2007, 7, 251-256
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Interaction and Assembly of HBV Structural Proteins: Novel Target Sites of Anti- HBV Agents - Infectious Disorders - Drug Targets 2007, 7, 251-256
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