How do the Anti-HIV drugs woks? By Tawitch Suriyo Master degree of Toxicology Mahidol University.
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Transcript of How do the Anti-HIV drugs woks? By Tawitch Suriyo Master degree of Toxicology Mahidol University.
How do the Anti-HIV drugs How do the Anti-HIV drugs woks?woks?
ByBy
Tawitch Suriyo Tawitch Suriyo
Master degree of Toxicology Master degree of Toxicology
Mahidol University Mahidol University
- How do anti HIV drugs work?
ContentContent
• The step of HIV life cycle that might be stopped.
• - The types of anti HIV drugs that we have now • Reverse Transcriptase Inhibito
rs
• Integrase Inhibitors
• Protease Inhibitors
The step of HIV life cycle that might be stopped.
11
2233
5566
441.Attachment
2.Reverse transcccccccc
3. &Integrase transcr i pt i on
4.Translation
5.viral protease
6. &assembly bcccccc
The step of HIV life cycle that might be stopped.
3.Integration,Transcript3.Integration,Transcriptionion
Viral DNA joins host DNA
Making multiple viral RNAs
Types of anti-HIV drugs that we have now.
•eeeeeee eeeeeeeeeeeee eeeeeeeeee
• Integrase Inhibitors (clinical trial)
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Reverse Transcriptase Inhibitor
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• - Non nucleoside analog E.g. Nevirapine,Delavirdine
Reverse Transcriptase Inhibitor
Nucleoside analog • These agents are both inhibitors a
nd substrates of RT, broad in famil - -y of 2’ 3’ dideoxynucleoside
• Need metabolism before functional
• Competitive inhibition with dNTP
• Incorperation into the viral DNA le ad to DNA termination
Reverse Transcriptase Inhibitor
Nucleoside analog : Zidovudine oreee + Thymidine analog - - -+ 3’ azido 2’,3’ dideoxythymidine + MW 267.24 + fomular C
10H13
N5
O4
Reverse Transcriptase Inhibitor
Nucleoside analog : Zidovudine oreee The mechanism of action of AZT +Metabolize of AZT
Reverse Transcriptase Inhibitor
Nucleoside analog : Zidovudine oreee -AZT TP
+competitive inhibit RT with respe ct t o TTP
+incorporate into growing chain ofDNA +AZT reduce the amount of dNTP (
-decreasing competition for AZT TP)
Reverse Transcriptase Inhibitor
Nucleoside analog : Zidovudine oreee -AZT TP
+Low concentration onhibit DNA polymerase
+distrub growing of cellular DNA c hai n
Reverse Transcriptase Inhibitor
Non-nucleoside analog• Structurally heterogenous
• - Active for HIV 1 only
• Not need metabolism before functional
• Interact with a nonsubstrate bindingsite
• Noncompetitive inhibition
Reverse Transcriptase Inhibitor
- Non nucleoside analog : Nevirapine
• Viramune (trade name)
• MW 2 6 6 .3
• fumular C15
H14
N4
O
Reverse Transcriptase Inhibitor
- Non nucleoside analog : Nevirapine
The machanism action of nevirapine
+bind directly to RT
+block RT activity (RNA depend - ent and DNA dependent DNA poly
merase) by distrub the RT’s catalyti c si t e (110 Asp,185Asp and 186 Asp tri
ad)
Reverse Transcriptase Inhibitor
- Non nucleoside analog : Nevirapine
+not compete with template or nuc leoside tritposphate
- +not inhibit HIV 2 RT and cellular D NA polymerase
Integrase Inhibitor
• HIV integrase is a viable therapeutic strateg y that will abort completion of the viral life cy
cle
• The commercial drug of this type not h ave yet now.
• Some drug just under clinical trial.
E.g. Zintevir currently in Phase I/II clinical trial.
Integrase Inhibitor
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• the formation of the ISC
• - the 3 ’ processing in reaction
• the DNA strand transfer
Integrase Inhibitor
e ee -eeeeeeeee• a protein of 32 kDa
• function for intergrate viral cDNA into human DNA
• recognizes specific sequence in LTR in viral cDNA
• composed of 3 functional domain
• active form is oligomer ( by oligomerization)
Integrase Inhibitor
e eeeeeeee eeeeeeeee ee eeeeeeeeeee eee eeeeeeeeeee• - triple helix mediated inhibition• inhibition IN by peptides derived from
combinatirial peptides chemistry.• Screening of chemical libraries and na
tural compounds.• - Inhibition by G quartet forming oligonucleotides
Integrase Inhibitor
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• oligonucleotide readly form stable co mplex with viral DNA
• triplex formation prevent catalytic fun ction of IN
Integrase Inhibitor
Inhibition IN by peptides derived from c ombinatirial peptides chemistry
• .find critical potion of IN by change am ino acid that make IN loss its functional
Integrase Inhibitor
eeeeeeeee ee eeee eeee eeeeeeeee eee natural compounds.
• -.find the chemical ( oligonucleotide ba se) that inhibit function of IN .
• Device into 3 categories• +DNA binding agent• +Polyhydroxylated aromatic compound• +Nucleotides
Integrase Inhibitor
- Inhibition by G quartet forming oligonueeeeeeeee
• oligonucleotides composed of base de oxyguanosine and thymidine
• -in presence of K+, Its form G quartet• - G quartet can inhibit HIV replication bc• +inhibit viral entry into cell• +and/or inhibition HIV IN
Integrase Inhibitor
• stable oligonucleotides of 17 nucleotides• composed only deoxyguanosine and t
hymidine,with single phosphorothioate internucleoside linkages at 5 ’ and 3 ’
end.•Fumular• - -5 3’ GTGGTGGGTGGGTGGGT ’
-177ZintevirorAR
Integrase Inhibitor
• Form a highly stable intra - molecular four stranded D
-NA contain two stacked Gquartet
• - Zintevir (G quartet) inhibi - t HIV 1 IN activity
-177ZintevirorAR
Integrase Inhibitor
The machanism of action of Zintevir• its inhibit integration in only step of th
e formation of ISC by• - +G quartet interact with IN• +it not bind to DNA binding domain
but its interact with zinc finger domain of I N
• +IN can’t form active form (oligomer)• +IN can’t bind with viral DNA
-177ZintevirorAR
Protease Inhibitor
Protease enzyme
• As aspartyl protease.
• Consist of 2 symmetric subunit
• each subunit consist 9 9 aminoacid
• single active site
• catalytic site conserve catalytic tr - -iads ( Asp Thr Gly)
Protease Inhibitor
Protease enzyme
• Cleavage polypeptide to functional e nzyme and structural protein
• - muation in catalytic site (Asp >Ala) cause immature virus (can’t infect ne
w cell)
• - HIV protease no cross reactivity with human cellular protease
Protease Inhibitor
Protease inhibitor
• Slow down the action of HIV protease
• e.g. Ritonavir, Indinavir,Saquinavir
Protease Inhibitor
Protease inhibitor
• Base on transitionstate mimetics of peptide substrate
• interact with catalytic residues and displace a structural water molecule
• the interaction protease and proteas e inhibitor complex cause enzyme not
functional properly.
Protease Inhibitor
Protease inhibitor : Ritonavir
• -Norvir (trade name) or ABT 583
• - - a white to light tan powder
• formular C37
H48
N6
O5
S2
• 72095MW .
Protease Inhibitor
Protease inhibitor : Ritonavir
• -A peptidomimetic inhibitor for HIV 1,2 protease
• Its directly interact with HIV protea se that cause this enzyme not functi
on
• the interaction is hydrophobic interaction
Protease Inhibitor
Protease inhibitor : Ritonavir
• hydrophobic interaction of P’3 isopr opylthiazolyl group of ritonavir with
- active side chain of valine 82 (V82) o f HIV protease
• mutation in V8 2 to Ala,Phe or Thr cause ritonavir resistance
Protease Inhibitor
Protease inhibitor : Ritonavir
• Its metabolized by CYP 3 A4
• and also a potent inhibitor of CYP 3A4
• inhibition of CYP by the unhindered nitrogen atom on the unsubatituted P
- 2 ’ 5 thiazolyl group with bind direct ly to the heme in the CYP active site
Protease Inhibitor
Protease inhibitor : Ritonavir
P3’ isopropylt hiazoly group
-P2’ 5 thia zoly group