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).