November 11, 2004
Some HIV Facts
• HIV – the Human Immunodeficiency Virus
is the retrovirus that causes AIDS
• HIV belongs to the retrovirus subfamily
• HIV attaches to cells with CD4 receptors
(T4 cells and macrophages).
HIV Life Cycle1
Step 1: Attachment of virus at the CD4
receptor and chemokine co-receptors CXCR4
Step 2: viral fusion and uncoating
Steps 3-5: Reverse transcriptase makes a
single DNA copy of the viral RNA and then
makes another to form a double stranded viral
Step 6: migration to nucleus
Steps 7-8: Integration of the viral DNA into
cellular DNA by the enzyme integrase
Steps 9-11: Transcription and RNA
Steps 12-13: Protein synthesis
Step 14: protease cleaves polypeptides into
functional HIV proteins and the virion
Step 15: virion budding
Step 16: Virion maturation
Anti- HIV Drug
Three types of drugs are
currently in clinical use:
1. nucleoside and
3. protease inhibitors
Nucleoside and Nucleotide
• Nucleoside analogs (NRTI) act as chain terminators
or inhibitors at the substrate binding site of RT
• NRTI’s must be phosphorylated (three steps) to their
5’-triphosphate form to become active inhibitors.
• Nucleotide analogs (NtRTI) already contain a
phosphate group and only go through 2 steps to
• The 5’-triphosphate of the NRTI’s compete with the
2’-deoxynucleoside’s 5’-triphosphate for binding to
reverse transcriptase leading to viral DNA chain
• There are currently 7 FDAapproved NRTI’s and one
• The first anti-HIV drug
approved was the NRTI known
as AZT or Zidovudine (1987).
• AZT was discovered as a
treatment of AIDS during a
screening process for the
identification of effective AIDS
• Antiviral selectivity due to
higher affinity for HIV RT than
human DNA polymerases.
• Non-nucleoside analog reverse transcriptase
inhibitors (NNRTI’s) inhibit viral DNA replication
by binding at the allosteric non-bonding site of RT,
causing a conformational change of the active site.
• NNRTI’s do not require bioactivation by kinases.
• Three NNRTI’s are currently approved for clinical
use in combination therapy: nevirapine,
delavirdine, and efavirenz
• During the reproduction cycle of HIV a specific
protease is needed to process GAG and POL
polyproteins into mature HIV components.
• If protease is missing noninfectious HIV is
• HIV protease inhibitors are specific to HIV
protease because it differs significantly from
• The 6 PI’s currently approved for clinical use were
all designed by using structure-based drug design
• The crystal structure of
HIV protease was first
obtained at Merck
• HIV protease is a 99
amino acid aspartyl
protease that functions as
a homodimer with one
• The active sites of
protease are hydrophobic.
• HIV PI’s target the peptide
linkages in the gag and
which must be cleaved by
• All approved PI’s contain
a hydroxyethylene bond
instead of a normal
• The hydroxyethylene bond
makes PI’s non-scissile
substrate analogs for HIV
• ABT-378 or lopinavir
was approved in 2000
for use in combination
with ritonavir (a PI)
• Ritonavir strongly
metabolism of ABT378
Some Alternative Therapies
• Virus adsorption inhibitors – interfere with
virus binding to cell surface by shielding the
positively charged sites on the gp-120
– Polyanionic compounds
• Viral coreceptor antagonists – compete for
binding at the CXCR4 (X4) and CCR5 (R5)
– bicyclams and ligands
Virus Adsorption Inhibitors
Cosalane was originally developed
as an anti-cancer agent by researchers
at Purdue University and the U.S.
National Cancer Institute8.
Cosalane was developed from a
chemical known as ATA
(aurintricarboxylic acid), which has
long been known to have
ATA is a mixture of different
polymers. Chemists took one of the
low molecular weight components of
ATA, and attached it to a steroid
molecule in order to target the
substance more effectively to the
surface of viruses and of cells.
The result was cosalane.
Cosalane binds to the HIV gp-120
Viral Coreceptor Antagonists
• Bicyclams are a type of viral
• They are very specific and
potent X4 coreceptor
• Bicyclams belong to a
class of macrocyclic
polyamines consisting of
two cyclam units linked by
an aliphatic bridge
• Bicyclams with an aromatic
linker apparently had higher
• One such compound is
• Combination therapy often called HAART is
standard care for people with HIV.
• Monotherapy created virus resistance to the
individual drug. Some combination therapies
increase the time it takes for the virus to become
• Combinations of a PI or NNRTI with one or two
NRTI’s is often recommended.
• Combination therapy may reduce individual drug
toxicity by lowering the dosage of each drug
• The combination of drugs chosen is based
on the history of each individual patient and
synergistic drug interactions.
• Some drugs compete with each other for
binding sites or enzymes.
– Example: zidovudine and stavudine
• both nucleoside analogs compete for the same
kinase. Stavudine is not phosphorylated because
zidovudine is preferred5.
Combination Therapy and Drug
• Some drug combinations can restore
sensitivity of the virus to drugs it was
previously resistant to.
– Example: lamivudine and zidovudine
• The HIV M184V mutation is resistant to lamivudine
but restores sensitivity to zidovudine resistant virus
Drug Toxicity and Side Effects
• All available antiretroviral drugs are toxic.
• Side effects of nucleoside analogs are lactic
acidosis and severe hepatomegaly with
steatosis (enlarged fatty liver)11.
• Other side effects of anti-HIV drugs include
pancreatitis, myopathy, anemia, peripheral
neuropathy, nausea, and diarrhea.
Reducing Drug Toxicity
• The use of combination therapy:
– Combining agents with favorable synergistic
properties allows a decrease in dose or dosing
– Ritonavir alone cause gastrointestinal side
effects but when used in combination with
other PI’s it can be administered at a lower
• An effective anti-HIV therapy is still
• Several possible targets are being studied
• The area of anti-HIV drugs has more room
for growth and the future for the discovery
of new effective drugs is promising.
NIAID HIV Life Cycle. http://www.niaid.nih.gov/daids/dtpdp/virpage1.htm (accessed Oct
De Clerq, E. New anti-HIV agents and targets. Med. Res. Rev. 2002, 22(6), 531-565.
El Kouni, M. H. Trends in the design of nucleoside analogues as anti-HIV drugs. Current
Pharmaceutical Design. 2002, 8(8), 581-593.
Block, J. H.; Beale, J. M. Antiviral Agents, Wilson and Gisvold’s Textbook of Organic
Medicinal and Pharmaceutical Chemistry, 11th ed; Lippincott Williams & Wilkins: Maryland,
2004; pgs 379, 943.
De Clerq, E.; Vandamme, A-M. Combination Therapy of AIDS. Birkhauser Verlag: Germany,
Brik, A.; Wong, C-H. HIV-1 protease: mechanism and drug discovery. Organic & Biomolecular
Chemistry. 2003, 1(1), 5-14.
De Clerq, E. New Developments in Anti-HIV Chemotherapy. Current Medicinal Chemistry.
2001, 8, 1543-1572.
cosalane website – look up
Ruell, J. A.; De Clercq, E.; Pannecouque, C. Synthesis and Anti-HIV Activity of Cosalane
Analogues with Substituted Benzoic Acid Rings Attached to the Pharmacophore through
Methylene and Amide Linkers. J. Org. Chem. 1999, 64, 5858-5866.
Labrosse, B.; Brelot, A.; Heveker, N.; Sol, N. Determinants for Sensitivity of Human
Immunodeficiency Virus Coreceptor CXCR4 to the Bicyclam AMD3100. J. Virol. 1998,
Simple FactSheet from the AIDS Treatment Data Network.
http://www.atdn.org/simple/abac.html (accssed Nov 2004).