Transcript Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI`s)

• HIV = Human Immunodeficiency Virus
• HIV is an RNA virus which contains two identical
strands of (+)ssRNA in its capsid.
• HIV is a retrovirus (i.e. viral RNS serves as template for
the synthesis of a complementary DNA)
• HIV infection usually progresses to AIDS
• AIDS = Acquired Immunodeficiency Syndrome.
• This stage of HIV infection is usually
characterized by opportunistic diseases,
including Pneumocystis carinii pneumonia,
Kaposi sarcoma, cytomegalovirus disease, etc.
• HIV-1 is responsible for AIDS in America,
Europe, and Asia
• HIV-2 occurs mainly in western Africa
• At present, anti-HIV drugs are aimed at two
targets: reverse transcriptase and HIV
protease.
• Good animation of HIV-1 Lifecycle:
• http://www.sumanasinc.com/webcontent
/animations/content/lifecyclehiv.html
• Link
Introduction to HIV treatment:
Resistance
• http://biocreations.com/animations/engli
sh_HIV/main.swf
HIV Lifecycle and Opportunities
for New Therapeutic Agents
• http://www.rochehiv.com/portal/eipf/pb/hiv/RocheHIV/demonstrationoffusioninhibition
Treatment of HIV
• When HIV replicates (makes new copies of
itself) it often makes mistakes.
• Taking two or more antiretrovirals at the
same time vastly reduces the rate at which
resistance develops
• The term Highly Active Antiretroviral Therapy
(HAART) is used to describe a combination of
three or more anti-HIV drugs.
Treatment of HIV
• Current classes of antiretroviral drugs
include:
– Nucleoside/Nucleotide Reverse Transcriptase
Inhibitors
– Non-Nucleoside Reverse Transcriptase
Inhibitors
– Protease Inhibitors
– Fusion or Entry Inhibitors
– Integrase Inhibitors
Nucleoside/Nucleotide Reverse
Transcriptase Inhibitors
• These were the first type of drug available to
treat HIV infection in 1987.
• NRTIs (also known as nucleoside analogues
or nukes) interfere with the action of an HIV
protein called reverse transcriptase, which
the virus needs to make new copies of itself.
• NRTIs are sometimes called the "backbone"
of combination therapy because most
regimens contain at least two of these drugs.
Antiretroviral Agents Currently Available (generic
name/Trade name) Nucleoside Analogs (NRTI’s)
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zidovudine/Retrovir(AZT, ZDV)
didanosine/Videx, Videx EC (ddI)
zalcitabine/HIVID (ddC)
stavudine/Zerit (d4T)
lamivudine/Epivir (3TC)
abacavir/Ziagen (ABC)
Nucleoside Reverse Transcriptase
Inhibitors (NRTI’s)
Zidovudine/Retrovir
(AZT, ZDV)
didanosine/Videx,
Videx EC (ddI)
zalcitabine/HIVID
(ddC)
Nucleoside Reverse Transcriptase
Inhibitors (NRTI’s)
Stavudine/Zerit
(d4T)
Lamivudine/Epivir
(3TC)
Abacavir/Ziagen
(ABC)
Nucleoside Reverse Transcriptase Inhibitors (NRTI’s)
Nucleotide Reverse Transcriptase
Inhibitor
Tenofovir disoproxil fumarate
Mechanism of action of AZT
• Link
• Link
Non-Nucleoside Reverse
Transcriptase Inhibitors
(NNRTI’s)
• Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTIs), started to be approved in 1997.
• Like the Nucleoside Inhibitors, NNRTIs (also known
as non-nucleosides) stop HIV from replicating
within cells by inhibiting the reverse transcriptase
protein.
Non-Nucleoside Reverse Transcriptase
Inhibitors (NNRTI’s)
• nevirapine/Viramune (NVP)
• delavirdine/Rescriptor (DLV)
• efavirenz/Sustiva (EFV)
•NNRTI’s are generally hydrophobic molecules that
bind to an allosteric binding site
•Binding to this allosteric site locks the neighboring
substrate-binding site into an inactive conformation.
•However, resistance to NNRTI’s can develop rapidly,
and thus they are used in combination with NRTI’s
• Link
Non-nucleoside reverse
transcriptase inhibitors
Efavirenz (Sustiva)
Delavirdine
(Rescriptor)
Protease Inhibitors
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indinavir/Crixivan
ritonavir/Norvirs
aquinavir/Invirase, Fortovase
nelfinavir/Viracept
amprenavir/Ageneras
elopinavir/ritonavir, Kaletra
Chemical Mechanism of HIV
Protease Hydrolysis
Link
Link
Modeling an inhibitor after the
transition state may result in a
tighter-binding inhibitor
But the actual transition state (in box above) is chemically
unstable, so a number of more stable “transition state
isosteres” have been devised.
HIV Protease Inhibitors
Indinavir/Crixivan
HIV Protease Inhibitors
Ritonavir/Norvir
HIV Protease Inhibitors
Nelfinavir/Viracept
Amprenavir
(Agenerase)
Lopinavir
Ritonavir
Development of saquinavir
Tipranavir
Tipranavir, or tipranavir disodium, is a nonpeptidic protease
inhibitor (PI) manufactured by Boehringer-Ingelheim under
the trade names Aptivus®. It is administered with ritonavir in
combination therapy to treat HIV infection and is given as two
250mg capsules together with 200mg of ritonavir twice daily.
Tipranvir
• Tipranavir has the ability to inhibit the
replication of viruses that are resistant
to other protease inhibitors and it
recommended for patients who are
resistant to other treatments.
Resistance to tipranavir itself seems to
require multiple mutations.
Animation of tipranavir, a new
HIV protease inhibitor
• http://biosingularity.wordpress.com/200
7/07/04/super-3d-animation-that-showsthe-mode-of-action-of-an-hiv-drug
Fusion or Entry Inhibitors
• Entry inhibitors prevent HIV from entering human
immune cells.
• There are several key proteins involved in the
HIV entry process:
– CD4, a protein receptor found on the surface of Helper T cells in
the human immune system, also called CD4+ T cells
– gp120, a protein on HIV surface that binds to the CD4 receptor
– CCR5, a second receptor found on the surface of CD4+ cells,
called a chemokine coreceptor
– CXCR4, another chemokine coreceptor found on CD4+ cells
– gp41, a HIV protein, closely associated with gp120, that
penetrates the cell membrane
Link
Link
Approved Entry Inhibitors
• Maraviroc (brand-named Selzentry, or
Celsentri outside the U.S.)
• Enfuvirtide (INN) is an HIV fusion
inhibitor, It is marketed under the trade
name Fuzeon (Roche).
Maraviroc
• Approved in April, 2007 and marketed by
Pfizer
Maraviroc
(Selzentry)
• Maraviroc is an entry inhibitor.
• Specifically, maraviroc blocks the chemokine
receptor CCR5 which HIV uses as a
coreceptor to bind and enter a human helper
T cell.
• Because HIV can also use another
coreceptor, CXCR4, an HIV tropism test such
as a trofile assay must be performed to
determine if the drug will be effective.
Enfuvirtide (Fuzeon)
• This drug is a small peptide of the following
sequence: Acetyl-YTSLIHSLIEESQNQ
QEKNEQELLELDKWASLWNWF-amide
•
• By virtue of its peptide nature, enfuvirtide is
marketed in injectable form. The lyophilised
enfuvirtide powder must be reconstituted by the
patient and administered twice daily by
subcutaneous injection
Enfuvirtide (Fuzeon)
• Enfuvirtide therapy costs an estimated
$25,000 per year in the United States.
• Its cost and inconvenient dosing
regimen are factors behind its use as a
reserve, for "salvage" therapy in
patients with multi-drug resistant HIV.
Approved HIV Integrase
Inhibitor
• Raltegravir (MK-0518, brand name
IsentressTM) is an antiretroviral drug
produced by Merck & Co, used to treat
HIV infection.
• It received FDA approval in October
2007, the first of a new class of HIV
drugs, the integrase inhibitors, to
receive such approval.
Raltegravir
(Isentress)
•Raltegravir is approved only for use only in individuals
whose infection has proven resistant to other HAART drugs.
•As with any HAART medication, raltegravir is unlikely to
show durability if used as monotherapy.
•Raltegravir is taken orally twice daily.
Assigned Reading
• An Introduction to Medicinal Chemistry
by Graham L. Patrick, pp. 440-486.
Homework Questions
• Draw the structure of AZT and discuss how the
nucleoside reverse transcriptase inhibitors (NRTIs)
interfere with DNA synthesis. Structurally, what must
happen to these molecules before they can perform their
function?
• Show the stepwise mechanism for the hydrolysis of a
peptide bond catalyzed by an aspartyl protease (such as
HIV protease) using arrows to depict the movement of
electrons.
• Draw the structure of saquinavir, the first HIV protease
inhibitor on the market, and discuss how/why this inhibitor
is effective against this viral enzyme.