HIV = Human Immunodeficiency Virus

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• 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

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• AIDS Acquired Immunodeficiency Syndrome.
• This stage of HIV infection is usually
  characterized by opportunistic diseases,
  including Pneumocystis carinii pneumonia, Kaposi
  sarcoma, cytomegalovirus disease, etc.

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• 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.

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• Good animation of HIV-1 Lifecycle
• http//www.sumanasinc.com/webcontent/animations/co
  ntent/lifecyclehiv.html
• Link

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Introduction to HIV treatmentResistance

• http//biocreations.com/animations/english_HIV/mai
  n.swf

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HIV Lifecycle and Opportunities for New
Therapeutic Agents

• http//www.roche-hiv.com/portal/eipf/pb/hiv/Roche-
  HIV/demonstrationoffusioninhibition

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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.

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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

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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.

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Antiretroviral Agents Currently Available
(generic name/Trade name) Nucleoside Analogs
(NRTIs)

• zidovudine/Retrovir(AZT, ZDV)
• didanosine/Videx, Videx EC (ddI)
• zalcitabine/HIVID (ddC)
• stavudine/Zerit (d4T)
• lamivudine/Epivir (3TC)
• abacavir/Ziagen (ABC)

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Nucleoside Reverse Transcriptase Inhibitors
(NRTIs)
didanosine/Videx, Videx EC (ddI)
zalcitabine/HIVID (ddC)
Zidovudine/Retrovir (AZT, ZDV)
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Nucleoside Reverse Transcriptase Inhibitors
(NRTIs)
Stavudine/Zerit (d4T)
Lamivudine/Epivir (3TC)
Abacavir/Ziagen (ABC)
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Nucleoside Reverse Transcriptase Inhibitors
(NRTIs)
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Nucleotide Reverse Transcriptase Inhibitor
Tenofovir disoproxil fumarate
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Mechanism of action of AZT

• Link
• Link

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Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTIs)

• 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.

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Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTIs)

• nevirapine/Viramune (NVP)
• delavirdine/Rescriptor (DLV)
• efavirenz/Sustiva (EFV)

• NNRTIs 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 NNRTIs can develop
  rapidly, and thus they are used in combination
  with NRTIs
• Link

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Non-nucleoside reverse transcriptase inhibitors
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Efavirenz (Sustiva)
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Delavirdine (Rescriptor)
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Protease Inhibitors

• indinavir/Crixivan
• ritonavir/Norvirs
• aquinavir/Invirase, Fortovase
• nelfinavir/Viracept
• amprenavir/Ageneras
• elopinavir/ritonavir, Kaletra

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Chemical Mechanism of HIV Protease Hydrolysis
Link Link
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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.
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HIV Protease Inhibitors
Indinavir/Crixivan
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HIV Protease Inhibitors
Ritonavir/Norvir
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HIV Protease Inhibitors
Nelfinavir/Viracept
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Amprenavir (Agenerase)
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Lopinavir
Ritonavir
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Development of saquinavir
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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.
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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.

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Animation of tipranavir, a new HIV protease
inhibitor

• http//biosingularity.wordpress.com/2007/07/04/sup
  er-3d-animation-that-shows-the-mode-of-action-of-a
  n-hiv-drug

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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

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Link Link
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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).

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Maraviroc

• Approved in April, 2007 and marketed by Pfizer

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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.

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Enfuvirtide (Fuzeon)

• This drug is a small peptide of the following
  sequence Acetyl-YTSLIHSLIEESQNQ
  QEKNEQELLELDKWASLWNWF-amide

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• 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

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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.

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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.

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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.

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Assigned Reading

• An Introduction to Medicinal Chemistry by Graham
  L. Patrick, pp. 440-486.

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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.