Anti-HIV Drugs. Cathy Molina November 11, 2004. Some HIV Facts. HIV – the H uman I mmunodeficiency V irus is the retrovirus that causes AIDS HIV belongs to the retrovirus subfamily lentivirus . HIV attaches to cells with CD4 receptors (T4 cells and macrophages). HIV Life Cycle 1.
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November 11, 2004
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).
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
- 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.
- 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.
- 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
- 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.
- 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.
- 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
- 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
Some Alternative Therapies
- Virus adsorption inhibitors – interfere with virus binding to cell surface by shielding the positively charged sites on the gp-120 glycoprotein
- Viral coreceptor antagonists – compete for binding at the CXCR4 (X4) and CCR5 (R5) coreceptors
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.
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.
- 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
- 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 to.
- 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 frequency
- Ritonavir alone cause gastrointestinal side effects but when used in combination with other PI’s it can be administered at a lower dose.
- 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.
- NIAID HIV Life Cycle. http://www.niaid.nih.gov/daids/dtpdp/virpage1.htm (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. http://www.atdn.org/simple/abac.html (accssed Nov 2004).