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Transcript
Anti-HIV Drugs
Cathy Molina
November 11, 2004
Some HIV Facts
• HIV – the Human Immunodeficiency Virus
is the retrovirus that causes AIDS
• HIV belongs to the retrovirus subfamily
lentivirus.
• 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
or CCR5
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
DNA
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
processing
Steps 12-13: Protein synthesis
Step 14: protease cleaves polypeptides into
functional HIV proteins and the virion
assembles
Step 15: virion budding
Step 16: Virion maturation
Anti- HIV Drug
2
Targets
Three types of drugs are
currently in clinical use:
1. nucleoside and
nucleotide reverse
transcriptase (RT)
inhibitors
2. non-nucleoside
reverse transcriptase
inhibitors
3. protease inhibitors
(PIs)
Nucleoside and Nucleotide
Analogs
• 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
become active.
• 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
termination3.
Nucleoside Analogs
• There are currently 7 FDAapproved NRTI’s and one
nucleotide analog.
• 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
treatments4.
• Antiviral selectivity due to
higher affinity for HIV RT than
human DNA polymerases.
Non-Nucleoside Analogs
• 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
5
Non-Nucleoside Analogs
Delavirdine
Benzoxazinone
Nevirapine
Protease Inhibitors
• 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
produced.
• HIV protease inhibitors are specific to HIV
protease because it differs significantly from
human protease.
• The 6 PI’s currently approved for clinical use were
all designed by using structure-based drug design
methods4.
HIV
6
Protease
• The crystal structure of
HIV protease was first
obtained at Merck
Laboratories.
• HIV protease is a 99
amino acid aspartyl
protease that functions as
a homodimer with one
active site.
• The active sites of
protease are hydrophobic.
Protease
7
Inhibitors
• HIV PI’s target the peptide
linkages in the gag and
gag-pol polyproteins
which must be cleaved by
protease.
• All approved PI’s contain
a hydroxyethylene bond
instead of a normal
peptide bond.
• The hydroxyethylene bond
makes PI’s non-scissile
substrate analogs for HIV
protease
Protease
7
Inhibitors
• ABT-378 or lopinavir
was approved in 2000
for use in combination
with ritonavir (a PI)
(Kaletra)
• Ritonavir strongly
inhibits the
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
glycoprotein
– Polyanionic compounds
• Viral coreceptor antagonists – compete for
binding at the CXCR4 (X4) and CCR5 (R5)
coreceptors
– 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
anti-HIV activity8.
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
protein.
Viral Coreceptor Antagonists
• Bicyclams are a type of viral
coreceptor antagonist.
• They are very specific and
potent X4 coreceptor
antagonists.
• 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
antiviral activity10.
• One such compound is
AMD3100.
Combination Therapy
• 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
resistant.
• 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
Combination Therapy
• 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
Resistance
• 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
mutants5.
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
frequency
– Ritonavir alone cause gastrointestinal side
effects but when used in combination with
other PI’s it can be administered at a lower
dose.
Conclusions
• An effective anti-HIV therapy is still
needed.
• Several possible targets are being studied
and tested.
• The area of anti-HIV drugs has more room
for growth and the future for the discovery
of new effective drugs is promising.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
NIAID HIV Life Cycle. http://www.niaid.nih.gov/daids/dtpdp/virpage1.htm (accessed Oct
2004).
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,
2004.
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,
6381–6388.
Simple FactSheet from the AIDS Treatment Data Network.
http://www.atdn.org/simple/abac.html (accssed Nov 2004).