Farmacologia dos antivirais.ppt Dúvidas denucci@gdenucci.com Arquivo Farmacologia dos antivirais.ppt Site www.gdenucci.com

Datas 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)

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

Datas 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

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

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

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

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

Retrovirus genome structure a) Integrated DNA provirus 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 LTR ~ 7-12 kb Host genomic DNA Gifford and Tristem - Virus Genes: 26:3, 291 – 315, 2003

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

Lentiviruses 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

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

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

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

env Proteínas de binding e entrada na célula glicoproteína gp 160 - gp120(SU) e gp41(TM) gp120 - binding; gp41 - fusão

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

Genes acessórios do HIV 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) CD4 Cells (per mm3) Length of Infection (yr)

Structure of the human immunodeficiency virus.

Ciclo do HIV

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

Enfuvirtide Nature 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

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

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

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 tratamento

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

Bases, nucleosídeos e nucleotídeos

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

AZT e Timidina

Inibidores nucleosídicos/nucleotídicos 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

bis (POM) - PMEA Adefovir dipivoxyl

Inibidores NÃO nucleosídicos/nucleotídicos 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)

Ciclo do HIV e sítios para tratamento

Integração 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 tratamento

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

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

Protease do HIV e inibidor

Protease do HIV e inibidor

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 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

Indinavir

Nelfinavir

Ritonavir

Saquinavir H

Amprenavir

Inibidores peptídicos da Protease 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

Atazanavir

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

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

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

Inibidores não peptídicos da Protease 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)

Mozenavir

Tripanavir

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

(A) and time of incubation (B) to THP-1 monocyte/macrophage cells. 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 response Total CD4 count I HIV II Latency III AIDS IV HAART Stage of autoimmune response Autoimmunity Reviews 1, (2002) 329-337

HBV replication cycle and site of action of several anti-HBV agents 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

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

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

Replication and IFN-resistance 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. 5’-UTR 3’-UTR Genome C E1 E2 NS2 NS3 NS4b NS5a NS5b p7 NS4a Proteins C E1 E2 NS2 NS3 NS4b NS5a NS5b p7 NS4a ? Functions Capsid protein Envelope proteins Metallo-protease Serine protease* RNA helicase Protease cofactor Replication and IFN-resistance RNA polymerase* Emerging host cell targets for hepatitis C therapy - Drug Discovery Today Volume 12, Numbers 5/6 March 2007

HCV Antiviral response Celular cofactors Viral targets Host cell HCV uses numerous cellular pathways and cofactors to complete its life cycle. HCV 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 Viral targets Host cell 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

HBsAg seroconversion occurs more frequently on HBV genotoype “A” compared to the other Genotypes. P>0.0008v 25.0 20.0 15.0 10.0 5.0 0.0 Peg-IFN-α2a Peg-IFN-α2a + lamivudine 5/23 P=0.018 5/23 4/165 3/162 1/82 0/11 0/76 0/9 A B C D A B C D Genotype dependece of HBsAg clearance Antiviral therapy and resistance with hepatitis B virus infection - World J Gastroenterol 2007 January 7; 13(1): 125-140

Pre-emptive lamivudine is associated with lower frequency and lower severity of hepatitis during chemotherapy. Date given in percent (%). 25.0 20.0 15.0 10.0 5.0 0.0 Lamivudine No lamivudine Grade 1 Grade 2 Grade 3 Grade 4 Hepatitis frequency and WHO severity on chemotherapy W/W.o Lam Antiviral therapy and resistance with hepatitis B virus infection - World J Gastroenterol 2007 January 7; 13(1): 125-140

Reduction of HBV viral load on Peg-interferon & lamivudine Viral load reduction at the end of treatment and at 24 wk follow-up in the different treatment arms. -1 -2 -3 -4 -5 -6 -7 -8 -2 -2.4 -2.6 -4.5 Peg + Lam -5.8 Peg Lam -7.2 End of treatment response 24 wk follow-up Reduction of HBV viral load on Peg-interferon & lamivudine Antiviral therapy and resistance with hepatitis B virus infection - World J Gastroenterol 2007 January 7; 13(1): 125-140

Median of HBV-DNA (pg/mL) Different response pattern on famciclovir. 500 400 300 200 100 Virological response pattern on famciclovir Median of HBV-DNA (pg/mL) Responder n = 6 Slow-responder n = 7 Non-responder n = 8 0 5 10 15 20 220 t (treatment)/wk 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

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 HBV-DNA reduction Inlfammation Fibrosis -1 -2 -3 -4 -5 ADV 10 mg (n = 171) ADV 30 mg (n = 173) Placebo (n = 167) Antiviral therapy and resistance with hepatitis B virus infection - World J Gastroenterol 2007 January 7; 13(1): 125-140

Prevalence of resistance on different antivirals, up to 2 year data. Resistence development on antivirals LAM ADV (LAM-R) ETV (Lam-R) FTC ADV ETV LdT 70 60 50 40 30 20 10 1 2 (yr) Antiviral therapy and resistance with hepatitis B virus infection - World J Gastroenterol 2007 January 7; 13(1): 125-140

Prevalence of resistance on different antivirals, up to 5 year data. 70 60 50 40 30 20 10 Lam ADV 1 2 3 4 5 (yr) Antiviral therapy and resistance with hepatitis B virus infection - World J Gastroenterol 2007 January 7; 13(1): 125-140

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

Properties of an ideal anti-HIV microbicide ● 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 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

Schematic representation of simulated transitions between the three protease forms. ‘Open’ Add ligand No ligand ‘Closed’ Bound protease ‘Semi-open’ Free protease Remove ligand 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 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

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 Foyes Principles of Medicinal Chemestry – Fifth edition – 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 Foyes Principles of Medicinal Chemestry – Fifth edition – 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

Famciclovir Penciclovir O N N N HN H2N H2N N N N N H3C-C-OCH2 HOCH2 O OH C-CH3 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 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

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