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HIV

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Title: HIV


1
HIV
  • HIV Human Immuno-deficiency 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.

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HIV Introduction
  • 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

10
HIV Lifecycle and Opportunities for New
Therapeutic Agents
  • http//www.roche-hiv.com/portal/eipf/pb/hiv/Roche-
    HIV/demonstrationoffusioninhibition

11
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.

12
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

13
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.

14
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)

15
Nucleoside Reverse Transcriptase Inhibitors
(NRTIs)
didanosine/Videx, Videx EC (ddI)
zalcitabine/HIVID (ddC)
Zidovudine/Retrovir (AZT, ZDV)
16
Nucleoside Reverse Transcriptase Inhibitors
(NRTIs)
Stavudine/Zerit (d4T)
Lamivudine/Epivir (3TC)
Abacavir/Ziagen (ABC)
17
Nucleoside Reverse Transcriptase Inhibitors
(NRTIs)
18
Nucleotide Reverse Transcriptase Inhibitor
Tenofovir disoproxil fumarate
19
Animation of action of AZT
  • http//www.uri.edu/pharmacy/animation/dnaHanleyAni
    m.htm
  • http//www.cat.cc.md.us/courses/bio141/lecguide/un
    it2/viruses/vircontrol.html

20
Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTIs)
  • Non-Nucleoside Reverse Transcriptase Inhibitors
    (NNRTIs), started to be approved in 1997.
  • Like the nukes, NNRTIs (also known as
    non-nucleosides or non-nukes) stop HIV from
    replicating within cells by inhibiting the
    reverse transcriptase protein.

21
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

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Non-nucleoside reverse transcriptase inhibitors
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Efavirenz (Sustiva)
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Delavirdine (Rescriptor)
30
Protease Inhibitors
  • indinavir/Crixivan
  • ritonavir/Norvirs
  • aquinavir/Invirase, Fortovase
  • nelfinavir/Viracept
  • amprenavir/Ageneras
  • elopinavir/ritonavir, Kaletra

31
Chemical Mechanism of HIV Protease Hydrolysis
32
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.
33
HIV Protease Inhibitors
Indinavir/Crixivan
34
HIV Protease Inhibitors
Ritonavir/Norvir
35
HIV Protease Inhibitors
Nelfinavir/Viracept
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Amprenavir (Agenerase)
38
Lopinavir
Ritonavir
39
Development of saquinavir
40
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.
41
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.

42
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

47
Link
48
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).

49
Maraviroc
  • Approved in April, 2007 and marketed by Pfizer

50
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.

51
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

54
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.

55
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.

56
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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