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... surface by shielding the positively charged sites on the gp-120 glycoprotein ... Cosalane binds to the HIV gp-120 protein. Viral Coreceptor Antagonists ... – PowerPoint PPT presentation

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Title: Anti-HIV%20Drugs

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
  • 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 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)

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
  • 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.

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.

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

Non-Nucleoside Analogs5
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
  • 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.

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
  • The active sites of protease are hydrophobic.

Protease Inhibitors7
  • HIV PIs target the peptide linkages in the gag
    and gag-pol polyproteins which must be cleaved by
  • 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

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

Some Alternative Therapies
  • Virus adsorption inhibitors interfere with
    virus binding to cell surface by shielding the
    positively charged sites on the gp-120
  • Polyanionic compounds
  • Viral coreceptor antagonists compete for
    binding at the CXCR4 (X4) and CCR5 (R5)
  • 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
  • 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
  • They are very specific and potent X4 coreceptor
  • 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
    NRTIs 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
  • 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
  • Ritonavir alone cause gastrointestinal side
    effects but when used in combination with other
    PIs it can be administered at a lower dose.

  • An effective anti-HIV therapy is still needed.
  • Several possible targets are being studied and
  • The area of anti-HIV drugs has more room for
    growth and the future for the discovery of new
    effective drugs is promising.

  1. NIAID HIV Life Cycle. http//
    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,
  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//
    (accssed Nov 2004).