Al-Azhar University

Faculty of High Education

New Aspects in
College of Pharmacy

HIV Antiviral
Drugs
Prepared By
Mohammed Baraka Abu
Iriban
01/20/10
Supervised By 1
 Introduction
A previously unknown immunodeficiency syndrome
that predominantly affected homosexual males was
first described in 1981.
It was associated with life-threatening Pneumocystis
carinii pneumonia and Kaposi’s sarcoma two
conditions that had been rare until then.
Similar cases of acquired immunodeficiency
syndrome (AIDS) were later observed in
hemophiliacs who had received clotting factor VIII
transfusions and in other recipients of blood or blood
products.
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 It was assumed that the agent responsible for
AIDS was transmitted by infectious, sexual,
and hematogenic routes, and later named
Human immunodeficiency virus (HIV).
Globally, about 14,000 individuals are newly
infected daily with one of the nine known
subtypes of human immunodeficiency virus
(HIV) that cause AIDS.

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 Structure of the genome and virion
HIV is a member of the lentivirus subfamily of
retroviruses.
All retroviruses contain reverse transcriptase, an
enzyme that transcribes single stranded genomic
RNA into DNA.
The protein encoding genes gag (group-specific
antigen), pol (reverse transcriptase and other
enzymes), and env (integral membrane proteins for
the lipid membrane envelope) are three additional
features that HIV shares with other retroviruses.

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 The genome contains vif (virion infectivity factor),
rev (regulator of expression of virion proteins), and
nef (negative regulatory factor), regulatory genes for
transcription or organization of the late replication
cycle.
The attachment of virus to the host cells involve two
steps: binding of gp120 to the second domain of the
CD4 molecule, and secondary binding to a
chemokines receptor after a conformational change.

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 Identification of cellular cofactors that promote
viral replication after virus entry as:
Tumor susceptibility gene 101 (TSG 101) and
endosome-associated complexes required for
transport (ESCRT) are host factors that may
mediate virus release.
There are also cellular factors that inhibit viral
replication as APOBEC 3G (apolipoprotein B
mRNA-editing enzyme, catalytic polypeptide-like
3G, also known as CEM15), which is a natural
defense against retroviral invasion.
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 Treatment strategies
All clinically approved anti-HIV drugs interfere
with the virus life cycle by inhibiting one of two
enzymes: the transcriptase or the protease, the two
enzymes play a vital role in the process of viral
replication inside the T-cell.
Due to the increase in development of resistance and
cross-resistance to the currently available anti-HIV
medications, efforts are directed towards developing
drugs capable of interfering with other steps of HIV
life cycle including its adsorption, entry, fusion,
uncoating, or integration with the T-cell
lymphocytes.
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 1-Inhibitors of viral entry
1.1-HIV vaccines
The most ideal approach to inhibit HIV binding to the
T-cells is to develop a vaccine that can neutralize the
virus in circulation.
Because of the nature of the disease, people infected
with HIV develop only low titers of neutralizing
antibodies and that presents a problem for vaccine
development.
Knowledge of the steps of the virus binding to the T-
cell, and discovery of the gp120, CD4, and the
chemokines as coreceptors for gp120 binding, lead to
development of more selective viral adsorption
inhibitors.
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 Viral adsorption inhibitors-1.2

1.2.1-Polyanionic compounds
Several polyanionic compounds of natural and
synthetic sources have been reported to inhibit gp120
binding to the cell membrane, as polysulfates,
polysulfonates, and polycaroxylates, all are believed
to exert their antiviral activity through inhibiting
gp120 binding to the CD4 receptor.
polyvinyl alcohol sulfate (PVAS, 1), polynaphthalene
sulfonate (2) and the polycarboxylate analog cosalane
(3) the most promising of polyanionic substances.

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 Soluble CD4 peptide fragments-1.2.2

Efforts to use soluble CD4 forms have

focused on CD4 conjugates with toxins.
Pro542 is a conjugation product of the
CD4 soluble receptors was found to be
more effective than the soluble CD4
alone in blocking HIV transmission in the
mouse model.

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Inhibitors of Gp120 binding to the T-cell-1.2.3
coreceptors
Gp120 coreceptors
The coreceptors CXCR4 and CCR5 are newly
discovered binding sites for gp120 on the T-cell
membrane surface.
These receptors naturally act as receptors for internal
ligands released normally in cases of inflammation or
immune responses, these ligands are generally
designated as chemokines (chemoattractant
cytokines).

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 The importance of inhibiting gp120 binding to these
coreceptors emerges from their role in the process of
activating the second viral envelope protein gp41
binding to the T-cell surface, which ultimately leads
to the virus entry.
1.2.3.1-Gp120-CXCR4 binding inhibitors
Bicyclam (AMD3100), the most interesting member
of this class, showed an in vitro anti-HN-1 activity
before the discovery of the HIV-1 coreceptors,
originally thought to inhibit a postentry step.
AMD3100 was subsequently found to bind
selectively to CXCR4.

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 Additional CXCR4 inhibitors include the
polypeptide derivatives ALX40-4C, T22,
T134, and T140.
There is a concern with all of these compounds
that long-term antagonism of CXCR4 function
could be detrimental to the immune function,
particularly in the B-cell and granulocyte
compartments.

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 Gp120-CCR5 binding inhibitors-1.2.3.2

CCR5 antagonists include TAK-779 and

PRO440, an anti-CCR5 monoclonal antibody,
these agents were found to block the binding
of chemokines to CCR5, consequently, they
have the potential to block HIV binding to
CCR5 and inhibit replication of CCR5-
dependent virus strains.

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 Inhibitors of viral fusion-2
The discover that gp41 anchors itself to the T-cell
membrane after the binding of gp120 to the coreceptors
through the hairpin structures HR1 and HR2 provided a
mechanistic basis for antiviral affects.
Synthetic peptides overlapping the two HR regions HR1
(e.g., DP-107 peptide ) and HR2 (e.g., DP-178 peptide)
were found to block HIV-1 replication in cell culture.
The betulinic acid derivative RPR103611 represents a non
peptide inhibitor for gp41 fusion.

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 lnhibitors for viral uncoating-3
loss of its nucleoprotein outer coat after fusion,
results in the release of its RNA genome into the
cytoplasm, uncoating is controlled by the p7
nucleocapsid protein (NCp7), which is a peptide
segment of the p17 protein.
NCp7 is a zinc-containing protein, and zinc-
displacing compounds were found to inhibit the virus
uncoating process.
Amantadine, NOBA, DIBA, SRR-SB3, dithiane, and
ADA that interfere with viral nucleoprotein
disassembly.
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 Inhibitors of HIV ribonuclease-4
( (RnaseH
The transcription of viral RNA copy to form the DNA
molecule (under the control of RT) is followed by a
second transcription of a positive strand of DNA to
form a double helix.
The tristranded product requires cleavage of the
original RNA strand from the double-helix DNA
molecule (the provirus).
RnaseH (a viral ribonuclease) is the enzyme
responsible for this step of removal of viral RNA
from DNA.
BBNH is a compound that inhibit RnaseH enzyme.
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 HIV integrase inhibitors-5
Integrase catalyze the insertion of the HIV-1 DNA
into the host cell genome.
L-chicoric acid, and the diketo acid derivatives L-
731,988 and L-708,906 are potent integrase
inhibitors.

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 lnhibitors of HIV gene expression-6
( (Transactivation inhibitors
Agents in this class inhibit the virus transcription
phase after viral DNA integration.
HIV uses the host genome to express its genes (gag,
env, pol), these genes translate the production of virus
structural proteins.
HIV gene expression occurs after the promotor LTR
(long terminal repeat) ends of the gene, by binding to
an activating viral protein called tat (transactivating).

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 Compounds that inhibit this process of gene
transactivation through inhibiting tat binding to the
promoter LTR end as fluoroquinoline K-12 and
temacrazine (bistriazoloacridone), inhibits viral
replication.

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 Inhibitors of virion assembly-7

The tripeptide Gly-Pro-Gly- NH, was

found to have anti-HIV activity.

Recent studies have shown that GPG

has a novel mechanism of action that
targets viral assembly and/or
maturation.

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 HIV drugs in clinical use

All currently available drugs for HIV therapy

belong to one of three classes of inhibitors:
1. Nucleoside reverse transcriptase inhibitors
(NRTIs).
2. Nonnucleoside reverse transcriptase inhibitors
(NNRTIs).
3. Protease inhibitors (PIS).

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 References
Color Atlas of Immunology, 2003.
The Process of New Drug Discovery
and Development, Second Edition,
2006.
Burger's Medicinal Chemistry and
Drug Discovery, sixth edition, volume
5.

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Thanks

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