An Overview of HIV Drugs: Past, Present, and Future Patrick Smollen Dr. Buynak Medicinal Chemistry March 2008

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  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  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 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 1 st drug to treat AIDS)  1995: First approved protease inhibitors  1998: First approved RTIs  2006: Atripola, the 1 st tablet consisting of 3 drugs is put on the market, greatly simplifying treatment

HIV Today: A Modern Pandemic USA (2005)

How is HIV contracted? DANGER  Health Care Setting  Tattoos / Piercings  Blood Transfusions  Blood Products  Mother to Child  Oral Sex  Vaginal Sex  Anal Sex  Injecting Drugs ALL CLEAR AHEAD  Sneezing / Coughing  Sharing Glasses  Showers / Pools  Protected Sex  Insects  Kissing*

The Life Cycle of HIV  Free Virus  Binding and Fusion  Infection  Reverse Transcription  Integration  Transcription  Assembly  Budding  Maturation

Introduction to Drugs HAART Entry Inhibitors Reverse Transcriptase Inhibitors (RTIs) Nucleoside/ Nucleotide RTIs (NRTIs) Non-Nucleoside RTIs (NNRTIs) Protease Inhibitors

Entry Inhibitors Enfuviritide Maraviroc

Closer Look: Maraviroc  1 st 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 Tenofir Disoproxil Competitive inhibitors No effect on host enzymes

Closer Look: Zidovudine  1 st 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 Nevirapine Delavirdine Efavirenz Noncompetitive inhibitors Only active against HIV-1 Easily vulnerable to resistance

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 Fosamprenavir Indinavir Atazanavir

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  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)

Vaccines  Preventative  Subunit Vaccines  Recombinant Vector Vaccines  DNA Vaccines  Therapeutic

The End Brunton, Lawrence L. et al. Goodman and Gilman’s The Pharmacological Basics of Therapeutics. 11th ed. McGraw-Hill pgs Flexner, Charles. “HIV Drug Development: The Next 25 Years.” Nature. Vol 6. pgs Dec Patrick, Graham L. An Introduction to Medicinal Chemistry. 3rd ed. Oxford University Press pgs