Antiviral Chemotherapy


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Antiviral Chemotherapy

  1. 1. Anti-Viral Chemotherapy <ul><li>Bacteria </li></ul><ul><li>Many antibiotics </li></ul><ul><li>Highly selective </li></ul><ul><li>Viruses </li></ul><ul><li>Use host cell metabolism </li></ul><ul><li>Selectivity difficult </li></ul><ul><li>Toxicity </li></ul>
  2. 2. Anti-Viral Chemotherapy <ul><li>Key is selectivity </li></ul><ul><li>Other problems </li></ul><ul><li>Toxicity </li></ul><ul><li>Rapid excretion </li></ul><ul><li>Rapid metabolism </li></ul><ul><li>Poor absorption </li></ul>
  3. 3. Anti-Viral Chemotherapy Ideal Drug <ul><li>Water soluble </li></ul><ul><li>Chemically and metabolically stable </li></ul><ul><li>Easily absorbed (apolar) </li></ul><ul><li>NOT </li></ul><ul><li>Toxic </li></ul><ul><li>Carcinogenic </li></ul><ul><li>Allergenic </li></ul><ul><li>Mutagenic </li></ul><ul><li>Teratogenic </li></ul>
  4. 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
  5. 5. Anti-Viral Chemotherapy Another consideration: Disease severity Rhinovirus v. Symptomatic rabies or Lassa fever
  6. 6. Anti-Viral Chemotherapy <ul><li>Reasons for continuing search for anti-virals versus vaccines: </li></ul><ul><ul><li>For many established diseases there is still no effective vaccine </li></ul></ul><ul><ul><ul><li>Rapid mutation (retroviruses) </li></ul></ul></ul><ul><ul><li>Or there are problems with the current vaccine </li></ul></ul><ul><ul><ul><li>Reassortment (influenza) </li></ul></ul></ul><ul><ul><li>New and emerging diseases - no vaccine available </li></ul></ul><ul><ul><li>Vaccine development takes many years </li></ul></ul><ul><ul><li>Disease that involve immunosuppression (AIDS, cancer, transplantation) </li></ul></ul>At present no drug completely suppresses viral replication (with possible exception of anti-HIV protease inhibitors)
  7. 7. Anti-Viral Chemotherapy <ul><li>A successful drug must interfere with: </li></ul><ul><li>A specific viral function e.g. enzyme necessary for viral life cycle </li></ul><ul><li>A cellular function that the virus needs in order to replicate </li></ul><ul><li>If interfere with cellular function either: </li></ul><ul><li>It must be crucial to virus but not the cell or </li></ul><ul><li>Only the virus-infected cell must be killed </li></ul><ul><li>(activation of drug in the infected cell only?) </li></ul>
  8. 8. Anti-Viral Chemotherapy <ul><li>Viral enzymes </li></ul><ul><li>Nucleic acid polymerases </li></ul><ul><ul><ul><li>DNA-dependent DNA polymerase - DNA viruses </li></ul></ul></ul><ul><ul><ul><li>RNA-dependent RNA polymerase - RNA viruses </li></ul></ul></ul><ul><ul><ul><li>RNA dependent DNA polymerase (RT) - Retroviruses </li></ul></ul></ul><ul><li>Protease (retrovirus) </li></ul><ul><li>Integrase (retrovirus) </li></ul><ul><li>Neuraminidase (orthomyxovirus) </li></ul>
  9. 9. Anti-Viral Chemotherapy <ul><li>1962 Idoxuridine </li></ul><ul><ul><li>Pyrimidine analog </li></ul></ul><ul><ul><li>Toxic </li></ul></ul><ul><ul><li>Topical - Epithelial herpetic keratitis (cornea) </li></ul></ul><ul><li>1983 Acyclovir </li></ul><ul><ul><li>Purine analog </li></ul></ul><ul><ul><li>Sugar modification </li></ul></ul><ul><ul><li>Chain terminator </li></ul></ul><ul><ul><li>Anti-herpes </li></ul></ul><ul><ul><li>Selective to virus-infected cells </li></ul></ul>1990’s Protease inhibitors
  10. 10. Binding Fusion Reverse transcription Nuclear localization Uncoating Integration Transcription Splicing RNA export Genomic RNA mRNA Translation Modification Budding Assembly Maturation Endocytosis Lysosome
  11. 11. Anti-Viral Chemotherapy <ul><li>Binding to surface receptor </li></ul><ul><li>At present no effective drugs in this class </li></ul>CD4-Ig2 (PRO542) - A more stable version of soluble CD4 is a tetrameric fusion protein of immunoglobulin G and CD4. It can reduce levels of virus in vivo AMD3100 - appears to bind to CXCR4 (fusin) RFI-641 (biphenyl triazine) active against RSV fusion <ul><li>Soluble CD4 - May make HIV more infective as results in chemokine receptor being the only necessary receptor </li></ul>
  12. 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
  13. 13. Anti-Viral Chemotherapy <ul><li>Endosome low pH often necessary for membrane fusion </li></ul><ul><ul><li>Lysosomotropic agents </li></ul></ul>Membrane Fusion
  14. 14. Anti-Viral Chemotherapy <ul><li>Amantadine: 1966 </li></ul><ul><li>Rimantadine: 1993 </li></ul><ul><li>Only effective against ‘flu A (200mg/day) </li></ul><ul><ul><li>Marginally effective therapeutically </li></ul></ul><ul><ul><li>Prophylaxis: Reduce flu by 90% </li></ul></ul><ul><li>Since disease usually mild and avoidable not used much here </li></ul><ul><li>Good alternative to vaccine for: </li></ul><ul><ul><li>Elderly </li></ul></ul><ul><ul><li>Immunocompromized </li></ul></ul><ul><ul><li>Allergic </li></ul></ul><ul><ul><li>Where causative strain not the vaccine strain </li></ul></ul>Affects M2 protein involved in activation of virus before release from cell Amantadine Rimantadine
  15. 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
  16. 16. Uncoating of core of membrane and non-membrane viruses <ul><li>Uncoating of picornavirus e.g. polio, echo, rhino </li></ul><ul><li>Stabilize coated virus? </li></ul>Anti-Viral Chemotherapy Arildone
  17. 17. Anti-Viral Chemotherapy N O O O N CH3 WIN 71711 (Disoxaril) <ul><li>Stabilizes picornaviruses - coated virus remains in cytoplasm </li></ul><ul><li>3-methylisoxazole group inserts in capsid VP1 and covers ion channel </li></ul>Similar mechanism: Pleconaril Good bioavailability – readily absorbed Crosses blood-brain barrier Old formulation worked poorly (oral) New formulation (nasal spray) Marketed (2004) by Schering-Plough 3-methyl isoxazole group
  18. 18. Anti-Viral Chemotherapy Human rhinovirus with WIN drug – embeds in VP1 VP1 VP1
  19. 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
  20. 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
  21. 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
  22. 22. Anti-Viral Chemotherapy <ul><li>Herpes thymidine kinase will phosphorylate any deoxynucleoside including drugs – as a result of its necessary non-specificity </li></ul><ul><li>Nucleoside analog may be given in non-phosphorylated form </li></ul><ul><ul><li>Gets drugs across membrane </li></ul></ul><ul><ul><li>Allows selectivity as only infected cell has enzyme to phosphorylate the drug </li></ul></ul>ACG P P P Cellular TK (where expressed) does not phosphorylate (activate) the drug
  23. 23. Anti-Viral Chemotherapy <ul><li>Need for activation restricts drug to: </li></ul><ul><li>Viruses such as HSV that code for own thymidine kinase </li></ul><ul><li>Virus such as cytomegalovirus and Epstein-Barr virus that induce cells to overproduce their own thymidine kinase </li></ul><ul><li>In either case it is the VIRUS-INFECTED cell that activates the drug </li></ul>
  24. 24. Anti-Viral Chemotherapy <ul><li>Thymidine kinase activates drug but phosphorylated drug inhibits the polymerase </li></ul><ul><li>Nucleotide analogs </li></ul><ul><li>Sugar modifications </li></ul><ul><li>Base modifications </li></ul><ul><li>Selectivity </li></ul><ul><li>Viral thymidine kinase better activator </li></ul><ul><li>Cellular enzyme may not be present in non-proliferating cells </li></ul><ul><li>Activated drug is more active against viral DNA polymerase that against cell polymerase </li></ul>
  25. 25. Anti-Viral Chemotherapy <ul><li>Guanine analogs </li></ul><ul><li>Acyclovir = acycloguanosine = Zovirax </li></ul><ul><li>Ganciclovir = Cytovene </li></ul><ul><ul><li>Activated by viral TK </li></ul></ul><ul><ul><li>Activated ACV is better (10x) inhibitor of viral DNA polymerase than inhibitor of cell DNA polymerase </li></ul></ul>Excellent anti-herpes drug Acyclovir Ganciclovir
  26. 26. Anti-Viral Chemotherapy <ul><li>Acyclovir: </li></ul><ul><ul><li>Chain terminator </li></ul></ul><ul><ul><li>Good anti-herpes drug </li></ul></ul>Normal DNA synthesis T P P G P C P A
  27. 27. Termination <ul><li>Also inhibits: </li></ul><ul><ul><li>Epstein Barr </li></ul></ul><ul><ul><li>Cytomegalovirus </li></ul></ul><ul><li>Acyclovir: </li></ul><ul><ul><li>Chain terminator </li></ul></ul><ul><li>Selective: </li></ul><ul><ul><li>Virus phosphorylates drug </li></ul></ul><ul><ul><li>Polymerase more sensitive </li></ul></ul>Anti-Viral Chemotherapy T P P G P C P A P A ACG P-P-P
  28. 28. Anti-Viral Chemotherapy <ul><li>Acyclovir very effective against: </li></ul><ul><ul><li>Herpes simplex keratitis (topical) </li></ul></ul><ul><ul><li>Latent HSV (iv) </li></ul></ul><ul><ul><li>Fever blisters – Herpes labialis (topical) </li></ul></ul><ul><ul><li>Genital herpes (topical, oral, iv) </li></ul></ul>Resistant mutants in thymidine kinase or DNA polymerase Appears not to be teratogenic or carcinogenic Ganciclovir very effective against cytomegalovirus – viral DNA polymerase is very sensitive to drug activated by cell TK
  29. 29. Anti-Viral Chemotherapy <ul><li>Adenine arabinoside (Ara-A) </li></ul><ul><li>Problems : Severe side effects </li></ul><ul><li>Resistant mutants (altered polymerase) </li></ul><ul><li>Chromosome breaks (mutagenic) </li></ul><ul><li>Tumorigenic in rats </li></ul><ul><li>Teratogenic in rabbits </li></ul><ul><li>Insoluble </li></ul><ul><li>Use: topical applications in ocular herpes simplex </li></ul>Competitive inhibitor of virus DNA polymerase which is much more sensitive than host polymerase
  30. 30. Anti-Viral Chemotherapy <ul><li>Adenine arabinoside </li></ul><ul><ul><li>HSV encephalitis </li></ul></ul><ul><ul><li>Neonatal herpes </li></ul></ul><ul><ul><li>Disseminated herpes zoster </li></ul></ul><ul><ul><li>Hepatitis B </li></ul></ul><ul><li>Poor in vivo efficacy: </li></ul><ul><ul><li>DEAMINATION </li></ul></ul>
  31. 31. Anti-Viral Chemotherapy Other sugar modifications: AZT azidothymidine DDI dideoxyinosine DDC dideoxycytidine
  32. 32. Anti-Viral Chemotherapy Base change analogs Altered base pairing Mutant DNA Resistant mutants Trifluorouridine Viroptic anti-HSV Idoxuridine
  33. 33. Anti-Viral Chemotherapy Fluoroiodo aracytosine has both a base and a sugar alteration
  34. 34. Anti-Viral Chemotherapy Cidofovir <ul><li>Cidofovir: </li></ul><ul><li>DNA chain terminator </li></ul><ul><li>DNA polymerase inhibitor </li></ul><ul><li>A acyclic nucleoside phosphonate (not a phosphate) - C-O-P bond in a nucleoside monophosphate replaced by a phosphonate (C-P) </li></ul><ul><li>More stable </li></ul>
  35. 35. Anti-Viral Chemotherapy Cidofovir <ul><li>Indicated: </li></ul><ul><li>CMV retinitis </li></ul><ul><li>May be useful: </li></ul><ul><ul><li>Pox: molluscum contagiosum virus </li></ul></ul><ul><ul><li>Polyoma: JC - progressive multifocal leukoencephalopathy </li></ul></ul><ul><ul><li>Adenovirus - gastroenteritis </li></ul></ul>Vaccinia in immunocompromisation? Used in on case: Eczema vaccinatum
  36. 36. Anti-Viral Chemotherapy Cidofovir
  37. 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
  38. 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
  39. 39. Anti-Viral Chemotherapy Sustiva (S) -6- chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3, 1-benzoxazin-2-one. DuPont Nevirapine
  40. 40. Anti-Viral Chemotherapy <ul><li>Nevirapine: Approved for AIDS patients Good blocker of mother to child transmission peri-natal - breast feeding </li></ul><ul><li>Single dose at delivery reduced HIV transmission by 50% </li></ul><ul><li>Single dose to baby by 72 hours </li></ul><ul><li>Efavirenz (Sustiva, DMP266) </li></ul><ul><li>In combination therapy will suppress viral load as well as HAART and may be better – Approved for AIDS patients </li></ul>
  41. 41. Anti-Viral Chemotherapy 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
  42. 42. Anti-Viral Chemotherapy <ul><li>Ribavirin </li></ul><ul><li>Guanosine analog </li></ul><ul><li>Non-competitive inhibitor of RNA polymerase in vitro </li></ul><ul><li>Little effect on ‘flu in vitro </li></ul><ul><li>Often good in animals but poor in humans </li></ul><ul><li>Aerosol use: respiratory syncytial virus </li></ul><ul><li>i.v./oral: reduces mortality in Lassa fever, Korean and Argentine hemorrhagic fever </li></ul>
  43. 43. Anti-Viral Chemotherapy May induce mutations in RNA viruses 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
  44. 44. Anti-Viral Chemotherapy Viral Protein synthesis: No inhibitors
  45. 45. Anti-Viral Chemotherapy <ul><li>Protein processing: </li></ul><ul><li>Proteolysis </li></ul><ul><li>Glycosylation </li></ul>
  46. 46. Anti-Viral Chemotherapy GAG Integrase Polymerase Protease GAG/POL polyprotein Retrovirus --- HIV
  47. 47. Anti-Viral Chemotherapy GAG Integrase Polymerase Protease folds and cuts itself free
  48. 48. Anti-Viral Chemotherapy GAG Integrase Polymerase Protease cuts at a site between the integrase and polymerase
  49. 49. Anti-Viral Chemotherapy GAG Integrase polymerase
  50. 50. Anti-Viral Chemotherapy Saquinavir
  51. 51. Anti-Viral Chemotherapy HIV aspartyl protease inhibitors Indinavir+AZT+3TC
  52. 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
  53. 53. Anti-Viral Chemotherapy Integrase Inhibitor Isentress Approved for use in adults by the USFDA in October, 2007
  54. 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
  55. 55. Relenza Tamiflu (oseltamivir)
  56. 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
  57. 57. Neuraminidase of virus removes sialic acid from cell surface thereby releasing virus
  58. 58. Virus hemagglutinin sticks new virus particle to sialic acid on cell surface Virus cannot escape from infected cell after neuraminidase inhibition
  59. 59. Anti-Viral Chemotherapy Zanamivir - Relenza Neuraminidase inhibitor Nasal spray Shortens symptoms by a few days Tamiflu: Oral neuraminidase inhibitor
  60. 60. <ul><li>NEURAMINDIASE INHIBITORS </li></ul><ul><li>TREATMENT </li></ul><ul><li>Oseltamivir is approved for treatment of persons aged > 1 year </li></ul><ul><li>Zanamivir is approved for treatment of persons aged > 7 years </li></ul><ul><li>PROPHYLAXIS </li></ul><ul><li>Oseltamivir and zanamivir can be used for chemoprophylaxis of influenza </li></ul><ul><li>Oseltamivir is licensed for use in persons aged > 1 year </li></ul><ul><li>Zanamivir is licensed for use in persons aged > 5 years </li></ul>Anti-Viral Chemotherapy
  61. 61. <ul><li>NEURAMINIDASE INHIBITORS </li></ul><ul><li>Development of viral resistance to zanamivir and oseltamivir during treatment has been identified </li></ul><ul><li>No transmission of neuraminidase inhibitor-resistant viruses in humans has been documented to date </li></ul><ul><li>Data are limited concerning the effectiveness of zanamivir and oseltamivir for treatment of influenza among persons at high risk for serious complications of influenza </li></ul>Anti-Viral Chemotherapy <ul><li>Among influenza virus- infected participants in 10 clinical trials, the risk for pneumonia among those participants receiving oseltamivir was approximately 50% lower than among those persons receiving a placebo </li></ul>