9 Anti-retroviral agents Flashcards
what is a retrovirus
RNA that went to DNA (carries reverse transcriptase)
what is critical for DNA synthesis
Oxygen atom
what is Azidothymidine
a Nucleoside analogue Reverse Transcriptase Inhibitor (NRTI)
what phosphorylates Azidothymidine:
All three phosphate groups are added dependent on the HOST cells
what is the effect of Azidothymidine
AZT-triphosphate acts as DNA chain terminator and will stick the reverse transcriptase = inhibit it
No oxygen atom so causes chain termination
does Azidothymidine work
AZT increase life from studies - 19 deaths, 18 in placebo arm
effect of treating patients with AZT before getting AIDs
no prolonged survival – the period of time that improve doesn’t last
Useful therapeutic life of about 6 months after this = no effect
what were the next NRTIs
ddC and ddI
what are ddC and ddI
2’3’dideoxy NAs developed
what is the toxicity of ddC and ddI
infect other organs (peripheral neuropathy, pancreatitis)
what led to the more sustained CD4 response
AZT + ddC or ddI
Give both drugs instead of just AZT = may improve life length
why is it better response giving AZT and ddC/ddI
Asking virus to acquire 9 mutations to become resistant to both as opposed to 5 to become resistant to AZT- take virus longer
what are NRTIs
Nucleoside and nucleotide reverse transcriptase inhibitors
what are NTRIs like
analogues of native nucleotides sharing the common motif of a lack of ‘3-OH group on their ribose ring
what do NTRIs require
Must be phosphorylated by cellular kinases before they can effectively exert their actions
NRTIs and native nucleosides
what are NNRTIs
Non-Nucleoside analogue Reverse transcriptase Inhibitors
what do NNRTIs do
Non-competitive RT inhibitors, induce conformational changes within reverse transcriptase
what can be given in combination therapy
Combination therapy (NRTI + NNRTI) achieves greater loss of viral load, sustained for longer
what do protease inhibitors do
bind to and inhibit HIV protease-mediated cleavage of HIV polyprotein precursors
effect of protein inhibitors on viruses
Virus particles can still be made but they are rendered non-infectious
what boosts protein inhibitors
Metabolised by CYP enzymes (use of ritonavir as CYP inhibitor to boost PIs)
what does HIV aspartyl protease do
cleaves gag and gag-pol polyproteins into their essential structural and enzymatic (RT and IN) components
HIV protease - Mechanism of resistance
mutations (a.a changes) modify the number and nature of points of contact between the PI and the protease molecule
what is the problem with protease inhibitors
a lot of these mutations are the same
If virus become resistant to one – likely will be resistant to the others
examples of available protease inhibitors
- Lopinavir (+ ritonavir) = Kaletra
- Atazanavir
what is ritonavir
booster for protease inhibitors
what does ritonavir do
Use a very small dose of ritonavir have no anti-HIV affect, but inhibits the degradation of the other protease inhibitors you’re going to give
NRTIs: adverse effects
block “RT”; They may inhibit the activity of normal cellular DNA polymerases
Viral entry
2 glycoproteins coming out from envelope – GP120 sticking out binds to CD4 – primary receptor molecule
Brings virus closer and binds to secondary receptor
gp41 bends so viral membrane brought into contact with cell membrane – fusion and virus enter cell
New antiretrovirals - HIV-1 Entry inhibitors
Enfuvirtide binds to half of gp41 and prevents the hinge activity
Enfuvirtide is a hinge inhibitor
Current anti-HIV therapy aim
put an absolute brake on ALL viral replication
– if virus is not replicating, then resistance cannot happen
HIV Drug resistance - cART effect
blocks the selection of mutants
how does cART block mutants
Multiple mechanisms are required for resistance to occur to all drugs in the regimen
how is the current anti-HIV therapy given
MUST be combination – Highly Active (HAART) or combination (cART) Antiretroviral Therapy
