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Strategie per lo sviluppo di antivirali

Explore strategies for antiviral development, targeting virus entry, replication, transcription, and assembly stages. Learn about key inhibitors and their mechanisms to combat viral infections effectively.

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Strategie per lo sviluppo di antivirali

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  1. 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

  2. Binding Reverse transcription Fusion Integration Endocytosis Transcription Nuclear localization Uncoating Splicing Lysosome RNA export Maturation Assembly Genomic RNA Modification Budding mRNA Translation

  3. Indice terapeutico: Minima dose tossica per le cellule Minima dose inibente il virus = 100-1000

  4. 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

  5. Inibitori dell’ingresso del virus

  6. 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: • Elderly • Immunocompromized • Allergic • Where causative strain not the vaccine strain Lysosomotropic drugs? Affects M2 Golgi ion channel involved in activation of virus before release from cell

  7. Inibitori della spoliazione

  8. 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?

  9. 3-methyl isoxazole group Chemotherapy 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

  10. Inibitori delle polimerasi v

  11. Chemotherapy • Adenine arabinoside(Ara-A) • Problems : Severe side effects • Resistant mutants (altered polymerase) • Chromosome breaks (mutagenic) • Tumorigenic in rats • Teratogenic in rabbits • Insoluble • Use: topical applications in ocular herpes simplex Competitive inhibitor of virus DNA polymerase which is much more sensitive than host polymerase

  12. Inibitori delle polimerasi v

  13. Chemotherapy • Guanine analogs • Acyclovir = acycloguanosine = Zovirax • Ganciclovir = Cytovene • Activated by viral TK • Activated ACV is better (10x) inhibitor of viral DNA polymerase than inhibitor of cell DNA polymerase Acyclovir Ganciclovir Excellent anti-herpes drug

  14. Inibitori delle polimerasi v

  15. Inibitori delle polimerasi v

  16. Inibitori delle polimerasi v

  17. Inibitori delle proteasi

  18. 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

  19. Inibitori delle polimerasi v

  20. 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

  21. 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

  22. Resistenza • Errori delle polimerasi virali (++ RT) • Elevata attività replicativa • Pressione selettiva del farmaco Talvolta: • Variante resistente minore attività replicativa mutazioni accessorie compensative

  23. Varianti TK – Varianti TK’ DNA pol* Più frequenti; attenuate Alterata specificità TK; rare Bassa affinità per l’analogo nucleosidico; molto rare HSV-Aciclovir

  24. Terapia HBV • Interferon Immunomodulatore 2’-5’ oligoadenilato sintetasi: m RNA

  25. Azione lamivudina Lamivudina lamivudina trifosfato enzimi cellulari DNA pol virale chain terminator

  26. 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

  27. Incidenza del fenomeno Virus erpetici • rara nei pazienti immunocompetenti; • 5-10%nei pazienti con AIDS e nei trapiantati • Resistenze multiple? • Ceppi trasmissibili?

  28. Incidenza del fenomeno • HBV-lamivudina 10-20 % pazienti con epatite cronica in trattamento per un anno • Virus influenzali-amantidina –frequente • Virus influenzali- zanamivir -rara

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