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Download Presentazione di PowerPoint - Corso di Laurea in Infermieristica
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Strategie per lo sviluppo di antivirali • • • • • • • • Attacco del virus al recettore Ingresso Spoliazione Trascrizione e traduzione Modifiche post-traduzionali Replicazione del genoma virale Assemblaggio/maturazione Liberazione Binding Reverse transcription Fusion Integration Transcription Endocytosi s Nuclear localization Uncoating Splicing Lysosome RNA export Maturation Genomic RNA Modification mRNA Translation Assembly Budding Indice terapeutico: Minima dose tossica per le cellule Minima dose inibente il virus = 100-1000 Chemotherapy 1962 Idoxuridine • Pyrimidine analog • Toxic • Topical - Epithelial herpetic keratitis 1983 Acyclovir • Purine analog • Sugar modification • Chain terminator • Anti-herpes • Selective to virus-infected cells 1990’s Protease inhibitors Inibitori dell’ingresso del virus Chemotherapy Amantadine: 1966 Rimantadine: 1993 Only effective against ‘flu A (200mg/day) • Marginally effective therapeutically • Prophylaxis: Reduce flu by 90% Since disease usually mild and avoidable not used much here Good alternative to vaccine for: Lysosomotropic drugs? • Elderly • Immunocompromized • Allergic • Where causative strain not the vaccine strain Affects M2 Golgi ion channel involved in activation of virus before release from cell Inibitori della spoliazione Chemotherapy Membrane Fusion • Endosome low pH often necessary for membrane fusion • Lysosomotropic agents Uncoating of core of membrane and non-membrane viruses • Uncoating of picornavirus e.g. polio, echo, rhino • Stabilize coated virus? Chemotherapy 3-methyl isoxazole group N O CH3 O WIN 71711 (Disoxaril) O N • Stabilizes picornaviruses coated virus remains in cytoplasm • 3-methylisoxazole group inserts in capsid VP1 and covers ion channel Similar mechanism: Pleconaril Inibitori delle polimerasi v Chemotherapy Adenine arabinoside (Ara-A) Problems : Severe side effects • Resistant mutants (altered polymerase) Competitive • Chromosome breaks (mutagenic) inhibitor of virus DNA • Tumorigenic in rats polymerase • Teratogenic in rabbits which is much more • Insoluble sensitive Use: topical applications in ocular herpes simplex than host polymerase Inibitori delle polimerasi v Chemotherapy Guanine analogs Acyclovir = acycloguanosine = Zovirax Ganciclovir = Cytovene • Activated by viral TK Acyclovir Ganciclovir Excellent anti-herpes drug • Activated ACV is better (10x) inhibitor of viral DNA polymerase than inhibitor of cell DNA polymerase Inibitori delle polimerasi v Inibitori delle polimerasi v Inibitori delle polimerasi v Inibitori delle proteasi Chemotherapy T-20 Peptides derived from gp41 can inhibit infection Probably block interaction of gp41 with cell membrane proteins during fusion T-20: In clinical trials, a nearly two log reduction in plasma HIV levels achieved Inibitori delle polimerasi v Chemotherapy Ribozymes RNA molecules that have catalytic properties among which are the specific cleavage of nucleic acids Heptazyme Ribozyme that cleaves hepatitis C RNA at highly conserved regions Recognizes and cuts all known types of the hepatitis C virus, thereby stopping viral replication Poor in clinic Resistenza • Ridotta sensibilità ad un farmaco dimostrata in un sistema di coltura in laboratorio, espressa come alterata IC50 o IC90 • Mutazioni specifiche nel genoma virale modificazioni nella proteina bersaglio del farmaco Resistenza • Errori delle polimerasi virali (++ RT) • Elevata attività replicativa • Pressione selettiva del farmaco Talvolta: • Variante resistente minore attività replicativa mutazioni accessorie compensative HSV-Aciclovir • Varianti TK – • Varianti TK’ • DNA pol* • Più frequenti; attenuate • Alterata specificità TK; rare • Bassa affinità per l’analogo nucleosidico; molto rare Terapia HBV • Interferon Immunomodulatore 2’-5’ oligoadenilato sintetasi: m RNA Azione lamivudina Lamivudina lamivudina trifosfato enzimi cellulari DNA pol virale chain terminator Metodi • Classico (test fenotipici): coltura del ceppo e saggio di riduzione delle placche in presenza del farmaco • Metodi molecolari (test genotipici): restriction fragment lenght polymorphism (RFLP); point mutation assay; sequenziamento;... gene chip technology Incidenza del fenomeno • • • • Virus erpetici rara nei pazienti immunocompetenti; 5-10%nei pazienti con AIDS e nei trapiantati Resistenze multiple? Ceppi trasmissibili? Incidenza del fenomeno • HBV-lamivudina 10-20 % pazienti con epatite cronica in trattamento per un anno • Virus influenzali-amantidina –frequente • Virus influenzali- zanamivir -rara
