Docstoc

Anti-viral drug therapy

Document Sample
Anti-viral drug therapy Powered By Docstoc
					      Anti-viral drug therapy
     The Nobel Prize in Physiology or Medicine 1988
      "for their discoveries of important
      principles for drug treatment"




Sir James W. Black                                    George H. Hitchings
1924-, UK                                             1905-1998, USA

                             Gertrude B. Elion
                             1918-1999, USA


                                                                    IPS
                                                                    Tetsuya Toyoda
                                                                    March 21, 2006
   Virus
                 Local infection                                                   Systemic
replication                                                                        infection
                virus
  in vivo
                                                                      lymphocyte
                                Koplik spot

                  Droplet
                  infection

                                                                    Local lymphnode


                                              Primary viremia


                                                                                                lypmocytepenia

                        brain    heart           lung        kidney    spleen       intestine




                                               Secondary viremia
                                                                                   Systemic lymphnodes


                                              Free virions    Infected monocyte



                                 antibodies

                   SSPE                        Subcutaneal haemangitis

Measles virus                                           Skin rush
  Host            Local infection                                                   Systemic

 defense         virus
                                                                                    infection


                                                                       lymphocyte
                                 Koplik spot

                   Droplet
   sIgA            infection

   IFN                                                               Local lymphnode

   (innate)
                                               Primary viremia


                                                                                                 lypmocytepenia
    IgG
    (acquired)           brain    heart           lung        kidney    spleen       intestine




                                                Secondary viremia
                                                                                                                  CTL
                                                                                    Systemic lymphnodes           (CD8)
                                               Free virions    Infected monocyte



                                  antibodies

                    SSPE                        Subcutaneal haemangitis

Measles virus                                            Skin rush
        Course of virus infection
                                                                Clinical symptoms

                                                          Catarrh       Koplic spot
                                              conjunctivitis
                                                                                        rash
                                                                                                       antibodies
                                                                                                       (IgG)

                                    Spread from the
                                    local epithelia                                                              acute disseminated
Entering in
                   Replication in the
                                                                                                                 encephalomyelitis
respiratory                                               Virus                                                  (ADEM)
                   local lymphatic
route
                   tissues                                replication


              0     1    2    3     4    5     6      7     8       9    10   11      12 13    14 15   16 17   18 19   20

                    Local                          Systemic infection
                  infection
                                             Date after infection
                   Acyclovir
Before Acyclovir




                   death           cure
After acyclovir




                           treat
   Viral specific step

1. Interferon a, b

2. Antivirals

3. siRNA

(antisence oligonucleotides)
SiRNA



        (RNA-induced silencing complexes)
    Replication of Influenza Virus
                     adsorption
                                    endocytosis
            Membrane fusion
                                                              Parent virus
                             endosome
                                                  HA、NA、M2
uncoating        nucleus                                      budding
                           NS1
                                   translation
      Transcription, replication

    mRNA                                         M1、NS2
                                                                  release
                                            PB1-F2




                                                             New virus
                                                                     vaccine
                 Anti-Influenza Drugs
                              adsorption
amantadine
                                         endocytosis
            Membrane fusion
                                                              Parent virus
                              endosome            HA、NA、M2
     uncoating
                  nucleus                                     budding
                            NS1                              Neuraminidase
                                    translation
       Transcription, replication                            inhibitor

     mRNA
                                                  M1、NS2
                   NP, RdRp                                       release
                                              PB1-F2




                                                             New virus
  Idea for anti-viral drug development


1.Viral specific metabolism: Acyclovir
   Nobel prize in 1988
   Elion, Hictching and Black
2.Molecular design from ternary structure of viral
  proteins: Zanamivir
   von Itzstein et al. Nature 363:418-23 1993.
 Anti-viral drugs


1.Anti-viral polymerase
2.Anti-viral protease
3.Anti-viral ion channel
4.Anti-viral neuraminidase
5. Anti-viral integrase
 Anti-viral drugs


1.Anti-viral polymerase
2.Anti-viral protease
3.Anti-viral ion channel       Viral enzymes

4.Anti-viral neuraminidase
5. Anti-viral integrase
                      Inhibitors
                      Antagonists
 Anti-viral drugs


1.Anti-viral polymerase
2.Anti-viral protease
3.Anti-viral ion channel
4.Anti-viral neuraminidase
5. Anti-viral integrase
Nucleotide analog
HSV

      HSV replication
HSV
           Action of acyclovir
 Guanine

                    Herpes virus TK
            acycl
                                                      Acyclo GMP
            ovir




                                               Cellular kinase

                        Herpes virus DNA pol




                                         Acyclo GTP
HSV
      Chain terminator 1




                  5’

                       3’
HSV
      Chain terminator 2




                  5’

                       3’
HBV
      hepadnaviral life cycle
HBV
      HBV pol inhibitor


           lamivudine triphosphate
HIV

       HIV replication

                                 processing



      integration




      RT

                    processing
nonnucleotide RT inhibitors (NNRTI)
HIV
      HIV-1 with NNRTI
HIV
      HIV RT mutation
 Anti-viral drugs


1.Anti-viral polymerase
2.Anti-viral protease
3.Anti-viral ion channel
4.Anti-viral neuraminidase
5. Anti-viral integrase
HIV
      HIV-1 protease




           indinavir
HIV mutation from protease inhibitors
 Anti-viral drugs


1.Anti-viral polymerase
2.Anti-viral protease
3.Anti-viral ion channel
4. Anti-viral neuraminidase
5.Anti-viral integrase
Flu


      Flu A M2 ion channel
Flu




      Pinto & Lamb, J Biol Chem. 2005
Flu


      FluA M2, Flu BM2




                 Pinto & Lamb, J Biol Chem. 2005
Flu

      Amantadine stucks in M2
Amino acid mutation of AD resistant M2




                    Hay et al. EMBO J. 4:3021 -3024, 1985
Flu
      Amino acid mutation of AD resistant M2 2




                          Hay et al. EMBO J. 4:3021 -3024, 1985
 Anti-viral drugs


1.Anti-viral polymerase
2.Anti-viral protease
3.Anti-viral ion channel
4.Anti-viral neuraminidase
5. Anti-viral integrase
Flu

      The active site of influenza A
            neuraminidase


                   Relenza       Tamiflu
                                oseltamivir
Flu


      Structure of GG167 (Zanamivir)
Combination of anti-virals


  1.HIV: HAART
  2.HCV: interferon + ribavirin
Targets of antiretroviral therapy
   Highly Active Anti-Retroviral Therapy
                 (HAART)

Antiretroviral regimens
2 nucleoside reverse transcriptase inhibitors, eg, zidovudine or stavudine + lamivudine
or didanosine
Plus either
1 non-nucleoside reverse transcriptase inhibitor: nevirapine or efavirenz
or
1 protease inhibitor: indinavir, nelfinavir or saquinavir soft gel
or
2 protease inhibitors, eg, ritonavir + saquinavir
3 nucleoside reverse transcriptase inhibitors: zidovudine + lamivudine + abacavir
     Recommended antiretroviral regimens for the initial treatment of chronic infection in
     adults (2001). Choice will depend on efficacy, tolerability, adherence, and resistance
     profile of regimen. Treatment guidelines are constantly reviewed and updated.
HIV




      Kaufmann et al. Sex Transm Inf 1999;75:218–224
HIV




      http://aidsinfo.nih.gov/
HIV
HIV
HIV


      HIV RT K65R and M184V
HIV


      HIV RT K65R
HIV


       AIDS-defining malignancies

      Kaposi’s sarcoma (KS)
      primary central nervous system lymphoma (PCNSL)
      AIDS-related non-Hodgkin’s lymphoma (ARL)

      Non-AIDS-defining malignancies
      HIV-related Hodgkin’s Lymphoma (HL)
      multiple myeloma (MM)
HCV


      HCV genome structures
                                                          Polymerase
  HCV                                                     inhibitors

inhibitors


NS3 protease
inhibitors




               Smith, R. M. & Wu, G. Y.Journal of Viral Hepatitis 10 (6), 405-412.

				
DOCUMENT INFO
Shared By:
Categories:
Stats:
views:307
posted:3/27/2008
language:English
pages:50