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An Overview of HIV Drugs: Past, Present, and Future. Patrick Smollen Dr. Buynak Medicinal Chemistry 5308 20 March 2008. What is HIV?. HIV = Human Immunodeficiency Virus Destroys CD4 cells (T-cells and macrophages) AIDS = Acquired Immunodeficiency Virus (~10 years after infection)

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an overview of hiv drugs past present and future

An Overview of HIV Drugs:Past, Present, and Future

Patrick Smollen

Dr. Buynak

Medicinal Chemistry 5308

20 March 2008

what is hiv
What is HIV?
  • HIV = Human Immunodeficiency Virus
  • Destroys CD4 cells (T-cells and macrophages)
  • AIDS = Acquired Immunodeficiency Virus (~10 years after infection)
  • HIV-1 = Europe, America, Asia
  • HIV-2 = Africa


advancement of hiv
Advancement of HIV
  • Progression of HIV*:
    • Stage I: HIV infection is asymptomatic and not categorized as AIDS
    • Stage II: includes minor mucocutaneous manifestations and recurrent upper respiratory tract infections
    • Stage III: includes unexplained chronic diarrhea for longer than a month, severe bacterial infections and pulmonary tuberculosis
    • Stage IV: includes toxoplasmosis of the brain, candidiasis of the esophagus, trachea, bronchi or lungs and Kaposi's sarcoma; these diseases are indicators of AIDS.
  • Symptoms: loss of energy and weight, frequent fevers and sweats, persistent or frequent yeast infections, persistent skin rashes or flaky skin, short-term memory loss, and bodily sores from Herpes infections
the history of hiv
The History of HIV
  • 1930s: Researchers believe a form of simian immunodeficiency virus jumped to humans in central Africa. The mutated virus is HIV-1.
  • 1960s: HIV-2, a viral variant found in West Africa, is thought to have transferred to people from sooty mangabey monkeys
  • 1964: The first retroviral agent (zidovudine) produced by Horwitz
  • 1966: Genetic studies of the virus indicate that, in or about 1966, HIV first left Africa, infecting a single person in US.
  • 1981: AIDS discovered in 5 gay men in LA (originally called GRID for Gay-Related Immune Deficiency)
the history of hiv1
The History of HIV
  • 1982: Name changed to AIDS (½ of infected persons not gay men)
  • 1985: HIV recognized as the cause of AIDS
  • 1985: Zidovudine shows anti-HIV properties and is approved for clinical trials (accepted in 1987 as the 1st drug to treat AIDS)
  • 1995: First approved protease inhibitors
  • 1998: First approved RTIs
  • 2006: Atripola, the 1st tablet consisting of 3 drugs is put on the market, greatly simplifying treatment
hiv today a modern pandemic
HIV Today: A Modern Pandemic

USA (2005)

how is hiv contracted
How is HIV contracted?


  • Sneezing / Coughing
  • Sharing Glasses
  • Showers / Pools
  • Protected Sex
  • Insects
  • Kissing*


  • Health Care Setting
  • Tattoos / Piercings
  • Blood Transfusions
  • Blood Products
  • Mother to Child
  • Oral Sex
  • Vaginal Sex
  • Anal Sex
  • Injecting Drugs
the life cycle of hiv
The Life Cycle of HIV
  • Free Virus
  • Binding and Fusion
  • Infection
  • Reverse Transcription
  • Integration
  • Transcription
  • Assembly
  • Budding
  • Maturation
entry inhibitors
Entry Inhibitors



closer look maraviroc
Closer Look: Maraviroc
  • 1st oral entry inhibitor
  • Blocks coreceptor CCR5
  • Resistance from one or more of several mutations in the V3 loop of gp120 or gp160
  • Possible Side Effects: Cough, Fever, Dizziness, Headache, Lowered BP, Nausea, and Bladder Irritation
reverse transcriptase inhibitors nrtis
Reverse Transcriptase Inhibitors: NRTIs

Tenofir Disoproxil

  • Competitive inhibitors
  • No effect on host enzymes
closer look zidovudine
Closer Look: Zidovudine
  • 1st approved drug for the treatment of AIDS
  • Phosphorylated by 3 cellular enzymes to form an active nucleotide triphosphate
  • Analogue of deoxythymidine where the 3’ hydroxyl is replaced by an azide group
  • The triphosphate is attached to the growing DNA chain, but cannot be extended.
  • Side effects may include anemia, nausea, headache, changes in body fat, and discoloration of nails.
reverse transcriptase inhibitors nnrtis
Reverse Transcriptase Inhibitors: NNRTIs




  • Noncompetitive inhibitors
  • Only active against HIV-1
  • Easily vulnerable to resistance
closer look efavirenz
Closer Look: Efavirenz
  • Made from X-ray crystallography of the RT binding site
  • Active against many variants of HIV
  • Replacing Lys-103 with asparagine (K103N mutation) causes resistance
  • Standard noncompetitive inhibitor
  • Possible Side Effects: Insomnia, Depression, Rash, Nausea, and Birth Defects
protease inhibitors
Protease Inhibitors




closer look fosamprenavir
Closer Look: Fosamprenavir
  • Increased water solubility and improved oral bioavailability
  • Metabolized to form amprenavir, which is the active ingredient
  • Because it must be metabolized, it is time released and requires less dosages (4 instead of 16 pills per day)
  • Possible Side Effects: Nausea, Vomiting, Diarrhea, Loose Stool, Hyperglycemia, and Fatigue
the future in treatment
The Future in Treatment
  • Integrase inhibitors (raltegravir and elvitegravir) in advanced development
  • CXCR4 inhibitors currently in development for HIV entry blockage
  • Drugs with a broader spectrum of activity and less vulnerable to induce resistance
  • More combination drugs like Atripola (efavirenz, tenofovir, emtricitabine) so that treatment can consist of a single pill taken once daily
  • Making drugs more affordable and available to more people ($1500/month and $618,000/lifetime)

  • Preventative
    • Subunit Vaccines
    • Recombinant Vector Vaccines
    • DNA Vaccines
  • Therapeutic
the end
The End

Brunton, Lawrence L. et al. Goodman and Gilman’s The Pharmacological Basics of Therapeutics. 11th ed. McGraw-Hill. 2006. pgs 1273-1314.

Flexner, Charles. “HIV Drug Development: The Next 25 Years.” Nature. Vol 6. pgs 959-966. Dec 2007.

Patrick, Graham L. An Introduction to Medicinal Chemistry. 3rd ed. Oxford University Press. 2005. pgs 450-471.