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Apresentação em tema: "Dúvidas Arquivo Farmacologia dos antivirais.ppt Site Dúvidas Arquivo Farmacologia dos antivirais.ppt."— Transcrição da apresentação:

1 Dúvidas Arquivo Farmacologia dos antivirais.ppt Site Dúvidas Arquivo Farmacologia dos antivirais.ppt Site

2 Datas importantes em AIDS 05/06/ casos de P carinii pneumonia em gays masculinos 16/07/ casos em hemofílicos 24/09/ AIDS 10/ casos em mulheres 10/12/ transfusão em crianças 17/12/ transmissão vertical (4 casos) 05/06/ casos de P carinii pneumonia em gays masculinos 16/07/ casos em hemofílicos 24/09/ AIDS 10/ casos em mulheres 10/12/ transfusão em crianças 17/12/ transmissão vertical (4 casos)

3 Datas importantes em AIDS 07/01/1983 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

4 Datas importantes AIDS - II didanosina e zalcitabina maior causa de morte anos (EUA) 1995 – saquinavir (inibidor de protease) queda de mortalidade nos EUA 2006 – expectativa de vida igual à pessoa sadia didanosina e zalcitabina maior causa de morte anos (EUA) 1995 – saquinavir (inibidor de protease) queda de mortalidade nos EUA 2006 – expectativa de vida igual à pessoa sadia

5 Incidência e morte por HIV nos EUA YearYear No. of Cases or Deaths Incidence of AIDS AIDS-related deaths

6 Retrovírus 4Material genético - RNA 4Necessita integração do genoma viral no DNA do hospedeiro (integrase) - provirus

7 Retroviridae 4Oncovirinae - oncongênicos e não oncogênicos 4Spumavirinae – infeções persistentes na ausência de doença clínica 4Lentivirinae – doença do sistema imunológica de progressão lenta

8 Lentiviruses 4Primatas - HIV-1 e SIV 4Não-primatas 4Não-primatas - FIV, vírus da anemia em infecções equinas, BIV 4Primatas - HIV-1 e SIV 4Não-primatas 4Não-primatas - FIV, vírus da anemia em infecções equinas, BIV

9 Accessory genes Accessory genes Accessory genes Accessory genes Accessory genes Accessory genes Accessory genes Accessory genes U3 R U5 gag pro pol env U3 R U5 MA CA NC PR RT IN SU TM LTR ~ 7-12 kb Retrovirus genome structure Host genomic DNA Gifford and Tristem - Virus Genes: 26:3, 291 – 315, 2003 a) Integrated DNA provirus

10 Retrovirus genome structure b) Viral genomic RNA PBS R U5 gag pro pol env PPT U3 R Leader Region Leader Region 5 CAP AAA 3 Gifford and Tristem - Virus Genes: 26:3, 291 – 315, 2003

11 Lentiviruses Structural Genes 4gag - proteínas estruturais e enzimas para a replicação viral 4pol - proteínas estruturais e enzimas para a replicação viral 4env – glicoproteínas do envelope viral

12 gag 4MA – montagem do vírion 4capsídeo – core hidrofóbico do vírion 4nucleocapsídeo – recobre o RNA viral 4Vários polipeptídeos - p1, p2 e p6

13 pol 4protease – lisa as proteínas expressas pelo gag e gag-pol. 4transcriptase reversa 4integrase

14 Transcriptase Reversa 4DNA-polimerase dependente de RNA 4RNAase H 4DNA-polimerase dependente de DNA

15 env 4Proteínas de binding e entrada na célula 4glicoproteína gp gp120(SU) e gp41(TM) 4gp120 - binding; gp41 - fusão

16 Genes regulatórios do HIV 4tat, rev 4Primeiras proteínas a serem sintetizadas após integração viral 4tat and rev aumentação a produção do mRNA viral

17 Genes acessórios do HIV 4Vif, vpr, vpu e nef 4vif - virion infectivity factor 4vpr - viral protein R - apoptosis 4nef – essencialp para a virulência do HIV - inibe a expressão do MHCI 4Vif, vpr, vpu e nef 4vif - virion infectivity factor 4vpr - viral protein R - apoptosis 4nef – essencialp para a virulência do HIV - inibe a expressão do MHCI

18 Sidney cohort (mutação no nef) Length of Infection (yr) CD4 Cells (per mm 3 )

19 Structure of the human immunodeficiency virus.

20 Ciclo do HIV

21

22 Ligação (binding) e entrada 4Glicoproteína do envelope viral – tropismo viral 4HIV-1 - CD4 & CCR5 ou CXCR4 4Glicoproteína do envelope viral – tropismo viral 4HIV-1 - CD4 & CCR5 ou CXCR4

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

24 Enfuvirtide 36 aminoácidos Liga-se a glicoproteína 41 viral 90 mg 2x/dia T1/2 – h

25 Budding of new virus particles Budding of new virus particles Anionic polymers Mode of action of enfuvirtide Nature Reviews, may 2003, volume 2 No 5 Proteolytic processing of viral proteins Proteolytic processing of viral proteins Transcription and translation translation Integration of viral DNA Into host genome Integration of viral DNA Into host genome Reverse transcription Virus entry Virus attachment to host cell Virus attachment to host cell CD4 inhibitors chemokine Receptor inhibitors Enfuvirtide CD4 inhibitors chemokine Receptor inhibitors Enfuvirtide NRTIs, NNRTIs Integretor inhibitor PIsPIs a)

26 CD4+target cell CD4+target cell gp120 Virus gp41 Enfuvirtide Fusion No Fusion Pre-hairpin intermediate Pre-hairpin intermediate Mode of action of enfuvirtide Nature Reviews, may 2003, volume 2 No 5 CD4 b)

27 Maraviroc - Drugs 2007; 67 (15):

28 Maraviroc Features and properties of maraviroc (CelsentriR; Selzentry®) Maraviroc - Drugs 2007; 67 (15):

29 Maraviroc Features and properties of maraviroc (CelsentriR; Selzentry®) Maraviroc - Drugs 2007; 67 (15):

30 Maraviroc Features and properties of maraviroc (CelsentriR; Selzentry®) Maraviroc - Drugs 2007; 67 (15):

31 Maraviroc Features and properties of maraviroc (CelsentriR; Selzentry®) Maraviroc - Drugs 2007; 67 (15):

32 Maraviroc Features and properties of maraviroc (CelsentriR; Selzentry®) Maraviroc - Drugs 2007; 67 (15):

33 Ciclo do HIV e sítios para tratamento

34 Transcrição reversa 4DNA linear duplo 4Enzima com baixa fidelidade – genoma viral altamente variável 4DNA linear duplo 4Enzima com baixa fidelidade – genoma viral altamente variável

35 Bases, nucleosídeos e nucleotídeos

36 Wikipedia, the free encyclopedia – DNA - Properties The chemical structure of DNA. Hydrogen bonds are shown as dotted lines.

37 AZT e Timidina

38 Inibidores nucleosídicos/nucleotídicos da transcriptase reversa (NRTI) 4Todos os nucleosídeos/nucleotídeos devem ser fosforilados (forma de tri-fosfato) 4Os 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 4Todos os nucleosídeos/nucleotídeos devem ser fosforilados (forma de tri-fosfato) 4Os 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

39 bis (POM) - PMEA Adefovir dipivoxyl

40 Inibidores NÃO nucleosídicos/nucleotídicos da transcriptase reversa (NNRTI) 4Interação alostérica, mas não no sítio catalítico 4Nevirapina, devalvirdina e efavirenz em uso clínico 4Emivirina em fase III. 4Induzem resistência rapidamente (evitada com NRTI) 4Interação alostérica, mas não no sítio catalítico 4Nevirapina, devalvirdina e efavirenz em uso clínico 4Emivirina em fase III. 4Induzem resistência rapidamente (evitada com NRTI)

41 Ciclo do HIV e sítios para tratamento

42 Integração 4Lisa os terminais 5 and 3 4cataliza integração no genoma do hospedeiro essencial para expressão gênica do retrovírus 4alvo terapêutico específico 4turnover baixo da enzima 4Raltegravir 4Lisa os terminais 5 and 3 4cataliza integração no genoma do hospedeiro essencial para expressão gênica do retrovírus 4alvo terapêutico específico 4turnover baixo da enzima 4Raltegravir

43 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

44 Ciclo do HIV e sítios para tratamento

45 Transcrição e síntese das proteínas virais 4Proteínas expressas pelo gens rev, tat and nef

46 Montagem do vírion e liberação 4RNA Viral e proteínas estruturais são empacotados 4Poliproteínas gag e pol são clivadas pela protease viral

47 Protease do HIV e inibidor AA

48 BB

49 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

50 Protease 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

51 IndinavirIndinavir

52 NelfinavirNelfinavir

53 RitonavirRitonavir

54 SaquinavirSaquinavir H

55 AmprenavirAmprenavir

56 Inibidores peptídicos da Pr otease 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

57 Atazanavir

58 Inibidores peptídicos da Protease do HIV Considerações 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

59 Efeitos Colaterais de Inidores Peptídicos de 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

60

61 Resistência aos inibidores peptídicos de 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

62 Inibidores não peptídicos da Pr otease 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)

63 Mozenavir

64 Tripanavir

65 Tipranavir /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/

66 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: print / online

67 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: print / online

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

69 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

70 Autoimmune disease and HIV I HIV I HIV II Latency II Latency III AIDS III AIDS IV HAART IV HAART Stage of autoimmune response Autoimmune response Autoimmune response Total CD4 count Autoimmunity Reviews 1, (2002)

71

72 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

73 Hepatitis B viral antigens and antibodies detectable in the blood following acute infection. Wikipedia, the free encyclopedia - Hepatitis B virus - Diagnosis

74 Hepatitis B viral antigens and antibodies detectable in the blood of a chronically infected person Wikipedia, the free encyclopedia - Hepatitis B virus - Diagnosis

75 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

76 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

77 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

78 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

79 Indication for observing and treating HBV Antiviral therapy and resistance with hepatitis B virus Infection - World J Gastroenterol 2007 January 7; 13(1):

80 Treatment options for chronic hepatitis B and their profile

81 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

82 Characteristics of the principal human IFN genes Interferon-based therapy of hepatitis C - Advanced Drug Delivery Reviews 59 (2007) 1222–1241

83 Characteristics of the principal human IFN genes (cont.) Interferon-based therapy of hepatitis C - Advanced Drug Delivery Reviews 59 (2007) 1222–1241

84 Characteristics of the principal human IFN genes (cont.) Interferon-based therapy of hepatitis C - Advanced Drug Delivery Reviews 59 (2007) 1222–1241

85 Alfa-interferon com PEG 2a: ligado a 40KD PEG, t1/2=100 hrs 2b: ligado a 12KD PEG

86 Tratamento da Hepatite C Interferon alfa com PEG + Ribavirin Inibidores de NS3-4a Protease Inibidores de NS5B polimerase

87 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

88 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

89 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

90 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

91 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. AGO2argonaute2. The Potential of RNA Interference – based Therapies for Viral Infections - Current HIV/AIDS Reports 2008, 5:33–39 Current Medicine Group LLC ISSN

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96 CE1E2 NS2 NS3 NS4bNS5aNS5b CE1E2 NS2 NS3 NS4bNS5aNS5b Genome Proteins Functions 5-UTR3-UTR Capsid protein Envelope proteins Metallo- protease Serine protease* RNA helicase Protease cofactor Replication and IFN-resistance RNA polymerase* NS4a p7 ? 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

97 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

98 Pros and cons of viral versus cellular targets Viral targetsCellular 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

99 5/23 0/76 3/162 0/9 5/23 1/82 4/165 0/11 P>0.0008v Peg-IFN-α2a Peg-IFN-α2a + lamivudine P= Genotype dependece of HBsAg clearance 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):

100 Grade 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):

101 End of treatment response 24 wk follow-up Reduction of HBV viral load on Peg-interferon & lamivudine Peg + Lam Peg Lam Viral load reduction at the end of treatment and at 24 wk follow-up in the different treatment arms. Antiviral therapy and resistance with hepatitis B virus infection - World J Gastroenterol 2007 January 7; 13(1):

102 t (treatment)/wk Median of HBV-DNA (pg/mL) Responder n = 6 Slow-responder n = 7 Non-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):

103 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):

104 HBV-DNA reductionInlfammationFibrosis ADV 10 mg (n = 171) ADV 30 mg (n = 173) Placebo (n = 167) 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):

105 Resistence development on antivirals LAM ADV (LAM-R) ETV (Lam-R) FTC ADV ETV LdT 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): (yr)

106 Antiviral therapy and resistance with hepatitis B virus infection - World J Gastroenterol 2007 January 7; 13(1): Lam ADV (yr) Prevalence of resistance on different antivirals, up to 5 year data.

107 Potential mechanisms (A–E) for HIV-1 transmission across the mucosal epithelium Microbicide drug candidates to prevent HIV infection - Lancet 2007; 369: 787–97

108 Target sites and mechanisms of microbicides Microbicide drug candidates to prevent HIV infection - Lancet 2007; 369: 787–97

109 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

110 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

111 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

112 Open Add ligand No ligand Closed Bound protease Semi-open Free protease Remove 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

113 The mechanisms whereby a CD8+ T cell kills a virus-infected host cell Pharmacology – fifth edition – fig. 46.2

114 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

115 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 Foyes Principles of Medicinal Chemestry – Fifth edition – fig 39.1

116 Antiviral Agents Interfering with Cellular Penetration and Early Replication Generic NameSpectrum of Activity AmantadineInfluenza A RimantadineInfluenza A Interferon Interferon α-2a Unlabeled use: Chronic hepatitis, CMV, HSV, Pappillomaviruses, Rhinovirses, others Interferon α-2bChronic hepatitis B and C, Unlabeled: many virus infections γ-Interferon ZanamivirInfluenza A; Influenza B Oseltamivir Influenza A; Influenza B Foyes Principles of Medicinal Chemestry – Fifth edition – tab 39.2

117 HIV Reverse Transcriptase (RT) Inhibitors Generic NameTrade name Nucleosides Reverse Transcriptase Inhibitors (NRTI) ZidovudineRitrovir DidanosineVidex (Dideoxyadenosine) ZalcitabineHivid StavudineZerit LamivudineEpivir Epivir HBV AbacavirZiagen Nonnucleosides Reverse Transcriptase Inhibitors (NNRTI) NevirapineViramune DelavirdineRescriptor EfavirenzSustiva Foyes Principles of Medicinal Chemestry – Fifth edition – tab 39.2

118 HIV Protease inhibitors Generic NameTrade name SaquinavirInvirase Fortovase RitonavirNorvir IndinavirCrixivan NelfinavirViracept AmprenavirAgenerase Lopinavir/ Kaletra Ritonavir Foyes Principles of Medicinal Chemestry – Fifth edition – tab 39.2

119 H 3 C-C-OCH 2 H2NH2N O N N N N O O C-CH 3 HOCH 2 H2NH2N HN N N N OH O FamciclovirPenciclovir Foyes Principles of Medicinal Chemestry – Fifth edition – pag 964

120 Type I IFN production and signaling pathways. Interferon-based therapy of hepatitis C - Advanced Drug Delivery Reviews 59 (2007) 1222–1241

121

122 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,

123 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,

124 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,

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


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