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Anti-HIV%20Drugs

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Title: Anti-HIV%20Drugs


1
Anti-HIV Drugs
  • Cathy Molina
  • November 11, 2004

2
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).

3
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

4
Anti- HIV Drug Targets2
  • Three types of drugs are
  • currently in clinical use
  • nucleoside and nucleotide reverse transcriptase
    (RT) inhibitors
  • non-nucleoside reverse transcriptase inhibitors
  • protease inhibitors (PIs)

5
Nucleoside and Nucleotide Analogs
  • Nucleoside analogs (NRTI) act as chain
    terminators or inhibitors at the substrate
    binding site of RT
  • NRTIs 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 NRTIs compete with
    the 2-deoxynucleosides 5-triphosphate for
    binding to reverse transcriptase leading to viral
    DNA chain termination3.

6
Nucleoside Analogs
  • There are currently 7 FDA-approved NRTIs 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.

7
Non-Nucleoside Analogs
  • Non-nucleoside analog reverse transcriptase
    inhibitors (NNRTIs) inhibit viral DNA
    replication by binding at the allosteric
    non-bonding site of RT, causing a conformational
    change of the active site.
  • NNRTIs do not require bioactivation by kinases.
  • Three NNRTIs are currently approved for clinical
    use in combination therapy nevirapine,
    delavirdine, and efavirenz

8
Non-Nucleoside Analogs5
Delavirdine
Benzoxazinone
Nevirapine
9
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 PIs currently approved for clinical use
    were all designed by using structure-based drug
    design methods4.

10
HIV Protease6
  • 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.

11
Protease Inhibitors7
  • HIV PIs target the peptide linkages in the gag
    and gag-pol polyproteins which must be cleaved by
    protease.
  • All approved PIs contain a hydroxyethylene bond
    instead of a normal peptide bond.
  • The hydroxyethylene bond makes PIs non-scissile
    substrate analogs for HIV protease

12
Protease Inhibitors7
  • ABT-378 or lopinavir was approved in 2000 for use
    in combination with ritonavir (a PI) (Kaletra)
  • Ritonavir strongly inhibits the metabolism of
    ABT-378

13
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

14
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.

15
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.

16
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
    NRTIs is often recommended.
  • Combination therapy may reduce individual drug
    toxicity by lowering the dosage of each drug

17
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.

18
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.

19
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.

20
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
    PIs it can be administered at a lower dose.

21
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.

22
References
  1. NIAID HIV Life Cycle. http//www.niaid.nih.gov/dai
    ds/dtpdp/virpage1.htm (accessed Oct 2004).
  2. De Clerq, E. New anti-HIV agents and targets.
    Med. Res. Rev. 2002, 22(6), 531-565.
  3. El Kouni, M. H. Trends in the design of
    nucleoside analogues as anti-HIV drugs. Current
    Pharmaceutical Design. 2002, 8(8), 581-593.
  4. Block, J. H. Beale, J. M. Antiviral Agents,
    Wilson and Gisvolds Textbook of Organic
    Medicinal and Pharmaceutical Chemistry, 11th ed
    Lippincott Williams Wilkins Maryland, 2004
    pgs 379, 943.
  5. De Clerq, E. Vandamme, A-M. Combination Therapy
    of AIDS. Birkhauser Verlag Germany, 2004.
  6. Brik, A. Wong, C-H. HIV-1 protease mechanism
    and drug discovery. Organic Biomolecular
    Chemistry. 2003, 1(1), 5-14.
  7. De Clerq, E. New Developments in Anti-HIV
    Chemotherapy. Current Medicinal Chemistry. 2001,
    8, 1543-1572.
  8. cosalane website look up
  9. 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.
  10. Labrosse, B. Brelot, A. Heveker, N. Sol, N.
    Determinants for Sensitivity of Human
    Immunodeficiency Virus Coreceptor CXCR4 to the
    Bicyclam AMD3100. J. Virol. 1998, 63816388.
  11. Simple FactSheet from the AIDS Treatment Data
    Network. http//www.atdn.org/simple/abac.html
    (accssed Nov 2004).
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