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Anti-HIV Drugs - Cathy MolinaNovember 11, 2004

Some HIV Facts. HIV

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Anti-HIV Drugs

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Anti-HIV Drugs

Cathy Molina

November 11, 2004

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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).

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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

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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)

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Nucleoside and Nucleotide Analogs

  • Nucleoside analogs (NRTI) act as chain terminators or inhibitors at the substrate binding site of RT

  • NRTI’s 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 NRTI’s compete with the 2’-deoxynucleoside’s 5’-triphosphate for binding to reverse transcriptase leading to viral DNA chain termination3.

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Nucleoside Analogs

  • There are currently 7 FDA-approved NRTI’s 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.

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Non-Nucleoside Analogs

  • Non-nucleoside analog reverse transcriptase inhibitors (NNRTI’s) inhibit viral DNA replication by binding at the allosteric non-bonding site of RT, causing a conformational change of the active site.

  • NNRTI’s do not require bioactivation by kinases.

  • Three NNRTI’s are currently approved for clinical use in combination therapy: nevirapine, delavirdine, and efavirenz

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Non-Nucleoside Analogs5




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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 PI’s currently approved for clinical use were all designed by using structure-based drug design methods4.

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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.

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Protease Inhibitors7

  • HIV PI’s target the peptide linkages in the gag and gag-pol polyproteins which must be cleaved by protease.

  • All approved PI’s contain a hydroxyethylene bond instead of a normal peptide bond.

  • The hydroxyethylene bond makes PI’s non-scissile substrate analogs for HIV protease

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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

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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

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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.

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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.

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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 NRTI’s is often recommended.

  • Combination therapy may reduce individual drug toxicity by lowering the dosage of each drug

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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.

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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.

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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.

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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 PI’s it can be administered at a lower dose.

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  • 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.

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  • NIAID HIV Life Cycle. (accessed Oct 2004).

  • De Clerq, E. New anti-HIV agents and targets. Med. Res. Rev. 2002, 22(6), 531-565.

  • El Kouni, M. H. Trends in the design of nucleoside analogues as anti-HIV drugs. Current Pharmaceutical Design.2002,8(8), 581-593.

  • Block, J. H.; Beale, J. M. Antiviral Agents, Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry, 11th ed; Lippincott Williams & Wilkins: Maryland, 2004; pgs 379, 943.

  • De Clerq, E.; Vandamme, A-M. Combination Therapy of AIDS. Birkhauser Verlag: Germany, 2004.

  • Brik, A.; Wong, C-H. HIV-1 protease: mechanism and drug discovery. Organic & Biomolecular Chemistry. 2003, 1(1), 5-14.

  • De Clerq, E. New Developments in Anti-HIV Chemotherapy. Current Medicinal Chemistry. 2001, 8, 1543-1572.

  • cosalane website – look up

  • 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.

  • Labrosse, B.; Brelot, A.; Heveker, N.; Sol, N. Determinants for Sensitivity of Human Immunodeficiency Virus Coreceptor CXCR4 to the Bicyclam AMD3100. J. Virol. 1998, 6381–6388.

  • Simple FactSheet from the AIDS Treatment Data Network. (accssed Nov 2004).