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Antiviral Drugs:
HIV treatment
Zach Laucis
April 17th, 2007
Outline
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Viruses
History of HIV/AIDS
Structure and life cycle of HIV
Therapy for HIV- highly active antiretroviral
therapy (HAART)
– Nucleoside reverse transcriptase inhibitors
– Non-nucleoside reverse transcriptase inhibitors
– Protease inhibitors
• Statistics
Viruses
Stages of life cycle
• Adsorption
– Virus binds to host cell
• Penetration and uncoating
– Contents of the capsid are introduced into the host cell
• Replication and transcription
• Synthesis and assembly of nucleocapsid
– Capsid proteins self assemble and essential DNA/RNA
and proteins are taken up
• Virion release
– Budding is when the viral proteins are introduced to the
host membrane and then pinched off.
History
• First discovered on June 5, 1981 in 5
homosexual men in LA.
• First given the name GRID—Gay-Related
Immune Deficiency. Changed to AIDS in 1982
when it was realized that over half of the people
infected were not homosexual men.
• French and American scientists discovered the
virus that caused AIDS within a year of each
other. President Reagan and President
Mitterrand met and agreed on the name of the
virus – Human Immunodeficiency Virus (HIV).
History
• HIV-1 is thought to have been first transmitted
to humans by wild chimpanzees in Cameroon.
• HIV-2 is believed to have been transmitted by
the Old World monkey Sooty Mangabey.
• The three earliest known findings of the HIV
are:
– Plasma taken from a male in the Congo in 1959
– In tissue taken from a 15 year old in St. Louis—he
died in 1969
– In tissue taken from a Norwegian sailor who died in
1976
Structure and life cycle
of HIV
• HIV is a retrovirus
– Contains two strands
of (+)ssRNA
• Contains reverse
transcriptase and
integrase.
– Integrase helps in the
insertion of HIV DNA
into host DNA
• Infects helper T cells
and macrophages—
immune system cells
Structure and life cycle
of HIV
• The outer membrane contains the proteins gp120 and gp41.
Both are important to adsorption and penetration.
• Gp120 binds to the transmembrane protein CD4 on the host
cell and then is removed by conformational changes.
• Gp41 then pulls the virus and host cell together allowing the
membranes to fuse.
• The capsid breaks down and the viral RNA and enzymes are
release into the cell.
• Reverse transcriptase converts the viral RNA into DNA. This
DNA is known as proviral DNA
• Integrase inserts the proviral DNA into the host’s DNA. Once
the proviral DNA is part of the host’s DNA, it is known as the
provirus and can remain dormant in the DNA
Structure and life cycle
of HIV
• When the provirus is transcribed, three main genes are
transcribed: env, gag, and pol.
• Three non-functional poly-proteins are made from these genes,
one from the env gene, one from the gag gene, and the last
one is from a combination of the gag and pol genes.
• The first produces gp120 and gp41 which are placed onto the
cell membrane. The other two poly-proteins move to the inner
cell membrane and block out host membrane proteins.
Budding occurs in this region of the membrane.
• The gag-pol protein releases protease by autocatalysing the
gag-pol protein. Protease then cleaves reverse transcriptase,
integrase, and other proteins.
• The capsid forms, with all viral RNA, essential enzymes, and
proteins in it. The complete virus then leaves the host cell.
HIV Therapy
• HAART includes three different classes of
drugs
– Nucleoside reverse transcriptase inhibitors
(NRTIs)
– Non-nucleoside reverse transcriptase
inhibitors (NNRTIs)
– Protease inhibitors (PIs)
• HAART delays the onset of AIDS. There is
no known cure for HIV or AIDS
Nucleoside Reverse
Transcriptase Inhibitors
NRTIs
• Since reverse transcriptase is specific to the
HIV virus, it serves as a good target.
• NRTIs are not active until the are taken into the
cell. There they are phosphorylated into a
triphosphate derivative.
NRTIs
Abacavir
• Can attack infected CNS cells
well
• It is phosphorylated to
carbovir triphosphate
• Viruses build resistance
quickly
• Can cause hypersensitivity
reaction
• Trade name is Ziagen by
GlaxoSmithKline
• Only NRTI that is a guanosine
analogue
Abacavir
NRTIs
Zidovudine
• Originally developed as
an anticancer drug, but
was the first approved
HIV drug in 1987.
• Inhibits further replication
because of the azide
group at the 3’ position.
• Side effects include
anemia and myelotoxicity
• Deoxythymidine
analogue
Zidovudine
NRTIs
Lamivudine
• An analogue of
zidovudine called
lamivudine was found to
be less toxic but still
effective as a NRTI.
• Inhibits replication
because of sulfur.
• Lamivudine can also
treat hepatitis B
• deoxycytidine analogue
Lamivudine
Non-nucleoside Reverse
Transcriptase Inhibitors
NNRTIs
• NNRTIs are non-competitive reversible
inhibitors.
• The allosteric binding site is next to the
substrate binding site. By binding to the
allosteric site, the shape of the substrate
binding is changed and becomes inactive.
• NNRTIs show a higher affinity to reverse
transcriptase than host DNA polymerases.
• Rapid resistance occurs by a mutation at Lys103 to asparagine.
NNRTIs
Nevirapine
• Developed by random
mass screening.
• Interacts using
hydrophobic and van der
Waals interactions.
• Causes mild to moderate
rashes with a chance of
life-threatening skin
reactions.
• In inactivated by the
mutation Val106Ala
Leu-100
Val-106
Val-179
Tyr-181
Tyr-188
Nevirapine
NNRTIs
Delavirdine
• Picked from a
screening of 1500
compounds
• Larger than binding
pocket, so it extends
into solvent.
• Mutations in Pro-236
can cause resistance
Lys-103
Pro-236
Lys-103
Tyr -188
Trp-229
Tyr-181
Tyr-188
Protease inhibitors
PIs
• Developed in the 1990’s using Xray crystallography.
• PIs do not need to be activated like
NRTIs
• PIs were designed using prior
research for a renin inhibitor.
Renin is a mammalian aspartyl
protease.
• They are transition-state inhibitors
• Designed to mimic the tetrahedral
intermediate and be able to bind to
the catalytic region—made up two
aspartic acids.
Tehrahedral
intermediate
N
OH
OH
PIs
Flap Region
Ile-50
Gly-48
H-O-H
Gly-48
O
P3
O
H
Ile-50’
P1
Asp-29
N
N
O
P2
Asp-29
H
N
O
P 1’
H
N
O
P 3’
Gly-27’
Gly-27
Asp-25
P 4’
O
H
N
N
H
P 2’
O
H
N
P 4
Gly-48’ Gly-48’
Asp-29’
Asp-25’
Catalytic Region
H
Asp-29’
O
PIs
Saquinavir
• It was the first PI to be
approved for use in 1995.
• Has to be taken with food
because of poor oral
bioavailability.
• Shows 100-fold selectivity
over human proteases
• Must be taken in high doses
because it binds easily to
plasma proteins
S2
S3
S1
S1’
S2’
PIs
Nelfinavir
• Lower molecular weight
than saquinavir and
increased aqueous
solubility—more potent
• Made by using part of
saquinavir
• Binds with protease like
saquinavir
S3
S1
S2
S1’
S2’
PIs
Ritonavir
• First developed as a PI, but
deemed useless because
of side effects.
• Discovered to inhibit the
cytochrome enzyme
CYP3A4.
• CYP3A4 is found in the
liver and metabolizes
protease inhibitors
• Given in low does, 100mg,
with the PI.
– Known as “boosting”
P2’
P3
Statistics
• HIV infection is now considered a pandemic
• Killed more than 25 million people since its
discovery
• Roughly 0.6% of the world’s population is
infected
• Globally 33.4-46 million people live with HIV
– 21.6-27.4 million of infected people live in subSahara Africa~64%
– 15% are in south and south east Asia.
• 2/3 of these infections are in India