Transcript HIV treatment

Nucleoside
Analogs
& HIV Treatments
October 4th, 2016
PHM142 Fall 2016
Instructor: Dr. Jeffrey Henderson
Meredith Ames
Insun Cho
Nathalie Dagenais
Zhiyi Molly Yang
Let’s take a
look!
Structure of
HIV
HIV Genome
ga
g
po
l
p17
p7
MATRIX
PROTEIN
NC
PROTEIN
P24
CAPSID
PROTEIN
p10
PROTEASE
env
p32
gp120
INTEGRASE DOCKING
PROTEIN
p66/51
REVERSE
TRANSCRIPTASE
gp41
TM
PROTEIN
Structure of
HIV
CHEMOKINE
RECEPTOR
AGONISTS
FUSION
INHIBITORS
REVERSE
TRANSCRIPTAS
E INHIBITORS
PROTEASE
INHIBITORS
INTEGRASE
INHIBITORS
HAART
Protease
Inhibitors
Reverse
Transcriptase
Inhibitors
PROTEASE
INHIBITORS
NONNUCLEOSIDE
REVERSE
TRANSCRIPTAS
E INHIBITORS
(NNRTIS)
NUCLEOSIDE
REVERSE
TRANSCRIPTAS
E INHIBITORS
(NRTIS)
Quick Review:
Reverse
Transcription
A Closer Look:
Reverse
Transcriptase
U
A
C
G
G
C
A
T
A
Zidovudine
(AZT)
T
Lamivudine(3TC
)
C
T
So Where do
Nucleoside Analogs
fit in?
Abacavir
Didanosine
(DDI)
GG
& Emtricitabine, Stavudine, Tenofovir…
A
G
C
G
G
T
C
A
T
AA
Limitations to
Treatment Safety
DNA Polγ
mtDNA
↓ ATP
↑ cell death
Limitations to
Treatment Efficacy
M184V
K65R
L74V
Why Use NRTIs?
Combination
therapy
↓ morbidity
↓ mortality
Adverse
events
& Resistance
Summary:
•HIV is a retrovirus with a genome that codes for 3 polyproteins, gp120 and gp41 are responsible for fusion into the host cell.
•There exists 6 types of antiviral drugs used in the treatment of HIV, these six types of drugs include nucleoside reverse transcriptase
inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, chemokine receptor antagonists (CCR5)
and lastly a relatively new class, HIV fusion inhibitors.
•HAART (Highly active antiretroviral therapy) is a combination therapy often used in the treatment of HIV, which is made up of a 3 or 4 drugs,
usually 2 nucleoside reverse transcriptase inhibitors with a non-nucleoside reverse transcriptase inhibitor, or alternatively one or two protease
inhibitors.
• Protease inhibitors: Protease inhibitors have a high affinity for the active site of HIV-1 protease and thus bind to the active site irreversibly.
This binding to the active site impairs the catalytic activity of HIV-1 protease resulting in immature viral particles that don’t properly package
into virions.
• NNRIs specifically target HIV-1 reverse transcriptase and thus exhibit specificity. This binding has effects on the active site of HIV-1 reverse
transcriptase, including conformational changes and changes in the “primer grip” in p66 (one of two subunits of the HIV-1 heterodimer) that is
responsible for positioning the DNA primer within the active site.
•Reverse Transcriptase: Pre-packaged Viral enzyme, heterodimer: subunits p66 & p51 of pol polyprotein; poor proof-reading capability (double
edged sword)
•2 Distinct Enzymatic Activities: DNA Polymerase (RNA & DNA templates) & Rnase H activity
•Nucleoside Analogs: Synthetic compounds developed to mimic their physiological counterparts; inhibit reverse transcription through their
incorporation into growing DNA strand (AZT: thymidine analog, 3TC: Cytidine analog)
•Mechanism of action:
– Active Transport into cell (some NAs may enter passively)
– 3-Step Metabolic Activation: phosphorylated by host cells kinases to active form, a 5’-trisphosphate derivative
– Inhibit Reverse Transcription through dual faceted approach:
• Competitive Inhibition
• Chain Termination (No 3’ Hydroxyl group: no phosphodiester linkage with incoming dNTP alpha-phosphate)
•Pros of NRTIs: effective treatment method when used in combination with other HIV treatments in HAART to decrease resistance mutations
•Cons of NRTIs:
1. Limitations in treatment safety – NRTIs inhibit DNA polymerase gamma which results in functional loss and subsequent decrease
in ATP production via oxidative phosphorylation and mitochondria-regulated apoptosis; Net effect is increase cellular dysfunction
and cell death
2. Limitations in treatment efficacy – NRTIs lose efficacy due to formation of mutant HIV variants, which confer resistance by two
mechanisms
i) discrimination between phosphorylated nucleoside analogues vs natural dNTP substrates results in decreased incorporation of
drugs
ii) increased reverse transcriptase phosphorlytic activity to excise drug from primer
Works Cited
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