4. Anti-Viral Chemotherapy Therapeutic index (T.I.) Minimum dose toxic to cell Minimum dose toxic to virus Effective drug: T.I. = 100-1000 at least www.freelivedoctor.com
5. Anti-Viral Chemotherapy Another consideration: Disease severity Rhinovirus v. Symptomatic rabies or Lassa fever www.freelivedoctor.com
12. Anti-Viral Chemotherapy 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 T-20 FUZEON (enfuvirtide) T-1249 Next generation: Different site from T-20 Membrane Fusion www.freelivedoctor.com
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15. ADAMANTANES Rapid emergence to amantadine and rimantadine because of M2 point mutation CDC Because of circulating resistant influenza virus strains, the use of Amantadine and Rimantadine is currently (2007) NOT recommended In the 2005-2006 influenza season, 92% of H3N2 influenza isolates had M2 mutation that would make them resistant www.freelivedoctor.com
19. Anti-Viral Chemotherapy Nucleic Acid Synthesis Polymerases are often virally encoded Other enzymes in nucleic acid synthesis e.g. THYMIDINE KINASE in Herpes Simplex www.freelivedoctor.com
20. Thymidine Kinase Deoxy-thymidine Deoxy-thymidine triphosphate Viral or cellular thymidine kinase adds first phosphate PO 4 PO 4 PO 4 Cellular kinases add two more phosphates to form TTP Anti-Viral Chemotherapy www.freelivedoctor.com
21. Anti-Viral Chemotherapy Why does Herpes simplex code for its own thymidine kinase? TK- virus cannot grow in neural cells because they are not proliferating (not making DNA) Although purine/pyrimidines are present, levels of phosphorylated nucleosides are low Allows virus to grow in cells that are not making DNA “ Thymidine kinase” is a misnomer Deoxynucleoside kinase NON-SPECIFIC www.freelivedoctor.com
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31. Anti-Viral Chemotherapy Other sugar modifications: AZT azidothymidine DDI dideoxyinosine DDC dideoxycytidine www.freelivedoctor.com
32. Anti-Viral Chemotherapy Base change analogs Altered base pairing Mutant DNA Resistant mutants Trifluorouridine Viroptic anti-HSV Idoxuridine www.freelivedoctor.com
37. Prodrugs e.g. Famciclovir Taken orally Converted by patient’s metabolism HSV thymidine kinase P Host kinase P P Penciclovir: Available as topical cream Glaxo-SmithKlein www.freelivedoctor.com
38. Anti-Viral Chemotherapy Non-nucleoside Non-competitive RT inhibitors Combination therapy with AZT Resistance mutations will be at different sites The most potent and selective RT inhibitors Nanomolar range Minimal toxicity (T.I. 10,000-100,000) Synergistic with nucleoside analogs (AZT) Good bio-availability Resistant mutants - little use in monotherapy www.freelivedoctor.com
41. Anti-Viral Chemotherapy www.freelivedoctor.com Phosphono acetic acid (PAA) Phosphono formic acid O O HO P C OH Binds pyrophosphate site of polymerase Competitive inhibitor 10 -100x greater inhibition of herpes polymerase Toxic: accumulates in bones, nephrotoxicity Rapid resistance Clinical trial: CMV in AIDS patients
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43. Anti-Viral Chemotherapy May induce mutations in RNA viruses www.freelivedoctor.com May inhibit RNA cap formation N N N HN H 2 N O CH 3 O CH 2 P P CH 2 O CH 3 P base
52. Anti-Viral Chemotherapy Indinavir (Merke) INDINAVIR + AZT + 3TC (HAART) No detectable HIV by PCR Before: 20,000 - 11,000,000 RNA copies /ml After: < 200-400 copies Lasts several years No replication No resistance www.freelivedoctor.com
53. Anti-Viral Chemotherapy Integrase Inhibitor Isentress Approved for use in adults by the USFDA in October, 2007 www.freelivedoctor.com
54. Anti-Viral Chemotherapy Influenza Requires neuraminidase to escape from cell Requires neuraminidase to penetrate mucus Zanamivir - RELENZA (fall 1997) Neuraminidase inhibitor Active against Influenza A and Influenza B www.freelivedoctor.com
56. Anti-Viral Chemotherapy After neuraminidase inhibition, ‘flu hemagglutinin binds to sialic acid on other virus particles: virus clumps OR virus sticks to mucous in respiratory tract www.freelivedoctor.com
57. Neuraminidase of virus removes sialic acid from cell surface thereby releasing virus www.freelivedoctor.com
58. Virus hemagglutinin sticks new virus particle to sialic acid on cell surface Virus cannot escape from infected cell after neuraminidase inhibition www.freelivedoctor.com
59. Anti-Viral Chemotherapy Zanamivir - Relenza Neuraminidase inhibitor Nasal spray Shortens symptoms by a few days Tamiflu: Oral neuraminidase inhibitor www.freelivedoctor.com
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