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Anti-HIV Drugs
Melissa Morgan
Medicinal Chemistry
November 23, 2004
The Life Cycle of HIV
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HIV causes the depletion of CD4 Tcells in the immune system
A CD4 receptor protein and a coreceptor, such as CCR5 or CXCR4, are
required for HIV to enter a cell
Fusion of the viral envelope with the
cell membrane allows the viral genome
and proteins to enter cell
Reverse-transcriptase produces a
cDNA copy of the viral RNA
Viral integrase incorporates viral cDNA
into host DNA as provirus
Transcription and translation of viral
proteins occur
Capsids assemble around viral
genomes and enzymes
New virus particles bud from host Tcell after assembly
Infected T-cell eventually dies
The Reverse-Transcriptase Enzyme
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The primary source of
scientific results on reversetranscriptase is conducting Xray crystallography studies on
the enzyme
The catalytic p66 subunit of
reverse-transcriptase has 4
domains, shown here as
different colored regions of the
ribbon diagram
Several classes of anti-HIV
drugs target the actions of
reverse-transcriptase
Reverse-transcriptase active site
The Classes of Anti-HIV Drugs
Nucleoside reverse-transcriptase inhibitors
(NRTIs)
 Nucleotide reverse-transcriptase inhibitors
 Non-nucleoside reverse-transcriptase
inhibitors (NNRTIs)
 HIV Protease Inhibitors
 Entry Inhibitors – includes the chemokine
receptor binders and the gp41-dependent
membrane fusion inhibitors
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Sites of Action of Anti-HIV Drugs
Nucleoside Reverse-Transcriptase
Inhibitors (NRTIs)
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2.
NRTIs must be phosphorylated 3 times by kinases to
form nucleoside triphosphates once inside the cell
This causes reverse-transcriptase to incorporate the
drug, rather than the natural nucleoside triphosphate,
thus terminating the growth of the DNA strand
Drugs in this class include zidovudine, didanosine,
zalcitabine, stavudine, lamivudine, abacavir, and
emtricitabine
2 mechanisms associated with HIV resistance to the
NRTIs:
impairment of the enzyme’s ability to incorporate an
analog into DNA
removal of the analog from the prematurely terminated
DNA strand
Zidovudine (AZT)
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AZT was originally developed in 1964 as a potential anti-cancer agent, but was
found to be ineffective
In the mid-1980s, AZT was found to be effective in fighting HIV as a result of a
screening process aimed at identifying anti-HIV agents
AZT works because it is an analog of thymidine that can be incorporated into
the DNA strand
Normally, the 3’ –OH group of thymidine binds to the phosphate group of the
next nucleotide in the DNA strand
However, AZT has an azido group instead of an –OH group, and the azido group
cannot bind to a phosphate group
As a result, reverse transcription stops once AZT is incorporated into the DNA
strand and incomplete proviral DNA is produced
Nucleotide Reverse-Transcriptase
Inhibitors
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Same mechanism of action as NRTIs, but only 2 phosphorylation events
are required to convert drug to its active triphosphate form
These drugs compete with normal DNA substrates to act as chain
termination inhibitors of reverse-transcriptase
The mutations that confer resistance to the NRTIs also confer
resistance to the nucleotide reverse-transcriptase inhibitors
The only FDA-approved drug in this class is tenofovir disoproxil
fumarate, a prodrug that is converted to its active form, tenofovir, once
in the body
Structure of tenofovir disoproxil fumarate:
Non-Nucleoside ReverseTranscriptase Inhibitors (NNRTIs)
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These drugs work by binding to an allosteric site, specifically
a hydrophobic pocket located near the catalytic domain of
reverse-transcriptase
The binding of the inhibitor restricts the activity and mobility
of the enzyme, thus blocking the polymerization of viral DNA
These drugs do not have to be activated by kinases to form
phosphate esters like the NRTIs
Increasing the amount of substrate does not displace the drug
from the enzyme; therefore, NNRTIs demonstrate noncompetitive inhibitory action with the enzyme
Drugs in this class include nevirapine, delavirdine, and
efavirenz
Mutations that confer resistance to NNRTIs are located in the
hydrophobic pocket targeted by the drugs, and they act by
reducing the affinity of the drug for the site
Examples of NNRTIs
Nevirapine
Efavirenz
Delavirdine
HIV Protease Inhibitors
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The 3-dimensional structure of the
HIV-1 protease was determined in
1988 when the enzyme was
crystallized
The structure consists of a dimer
demonstrating precise dual
rotational C2 symmetry
The active sites are located in loops
that approach the center of the
dimer
HIV-1 protease develops the gag
and gag-pol polyproteins into
functional viral proteins & enzymes
The structures of the HIV protease
inhibitors are derived from the
natural peptidic substrates of the
HIV-1 protease
These drugs work by binding the
active site of HIV-1 protease,
thereby preventing the enzyme from
releasing individual viral proteins
HIV-1 protease with bound inhibitor
Examples of HIV
Protease Inhibitors
Saquinavir
Indinavir
Ritonavir
Amprenavir
HIV Entry Inhibitors
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The HIV entry inhibitors class includes the chemokine
receptor binders and the gp41-dependent membrane fusion
inhibitors
The HIV-1 envelope glycoprotein contains 2 non-covalently
coupled subunits, gp120 and gp41
gp120 controls target cell recognition and viral tropism
through interaction with a CD4 receptor and a co-receptor,
such as CCR5 or CXCR4, on the target cell
Co-receptors are members of the seven-transmembranespanning, G-protein-coupled receptor family, whose normal
function is to bind chemokines
Thus, gp120 is the subunit involved in the mechanism of
action of the chemokine receptor binding drugs
gp41 promotes fusion of the viral and cellular membranes
HIV Entry Inhibitors
Chemokine Receptor Binders
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Different strains of HIV-1
employ different co-receptors for
entry
The R5 strain utilizes the CCR5
co-receptor
The X4 strain utilizes the CXCR4
co-receptor
The R5X4 strain utilizes both
CCR5 and CXCR4 co-receptors
AMD-3100 hinders only the X4
strains of HIV-1 because it acts
as a selective inhibitor of the
CXCR4 co-receptor
TAK-779 blocks only the R5
strains of HIV-1 because it
demonstrates selective binding
to the CCR5 co-receptor
Both of these drugs are
currently in clinical trials
gp41-Dependent Membrane
Fusion Inhibitors
Fusion of the viral and cellular membranes elicits several conformational
changes that lead to the formation of the trimer-of-hairpins structure in
gp41
 The drugs in this class prevent membrane fusion by interfering with the
development of the trimer-of-hairpins structure
 It is believed that a mechanism of dominant-negative inhibition,
involving C-peptides, prevents this development
 One drug in this sub-class is enfuvirtide
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Enfuvirtide (Fuzeon)
Enfuvirtide is the only FDA-approved drug in the subclass of gp41-dependent membrane fusion inhibitors
 Enfuvirtide is a 36-amino acid peptide derived from the
HR2 region of gp41
 During membrane fusion, HR2, a distal hydrophobic
region of gp41, folds onto HR1, a proximal hydrophobic
region, in order to shorten the molecule.
 Enfuvirtide binds to HR1 and inhibits the formation of
the gp41 conformation necessary for fusion by
interfering with the interaction between the COOH- and
NH2-terminal repeat
 Resistance to enfuvirtide arises as a result of mutations
in a 10-amino acid motif in the HR1 region of gp41
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Combination Therapy - HAART
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Combinations of antiretroviral
drugs are also used for the
treatment of HIV
Highly active antiretroviral therapy,
or HAART, enables the pairing of
different types of drugs that may
control or prevent the emergence
of drug-resistant HIV strains
HAART regimens typically include 3
drugs, usually 2 nucleoside
reverse-transcriptase inhibitors and
either a protease inhibitor or a
non-nucleoside reversetranscriptase inhibitor
Future Anti-HIV Drug Targets
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One step of the HIV life cycle that may be a future drug
target is the RNase H activity of reverse-transcriptase.
Screenings of compounds may enable researchers to
discover a drug that can attack that target.
Another potential drug target relates to the HIV virion
infectivity factor (VIF). It is believed that the VIF
prevents the activity of a cellular factor that normally
stops the creation of infectious virions.
A final stage of the HIV life cycle that may be targeted
by future drugs is the import of nucleic acids. Nuclear
uptake is facilitated by virion proteins that may function
with importin B and other nuclear import receptors
These potential drug targets will undoubtedly be
exploited in the coming years
Summary of Anti-HIV Drugs
Conclusion
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Current drugs provide many
options to patients, through
both monotherapy and HAART
HAART produces particularly
promising clinical results
Future HIV drug treatment
options must continue to
focus on the development of
drugs that are less likely to
encourage mutations that
confer resistance
Hopefully, more successful
drugs to fight HIV and a
vaccine will be among the
developments in the future of
HIV research