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)
 HIV-1 = Europe, America,
Asia
 HIV-2 = Africa
*http://en.wikipedia.org/wiki/Aids#Diagnosis
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 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
USA (2005)
How is HIV contracted?
DANGER
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Health Care Setting
Tattoos / Piercings
Blood Transfusions
Blood Products
Mother to Child
Oral Sex
Vaginal Sex
Anal Sex
Injecting Drugs
ALL CLEAR AHEAD
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Sneezing / Coughing
Sharing Glasses
Showers / Pools
Protected Sex
Insects
Kissing*
The Life Cycle of HIV
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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)
Protease
Inhibitors
Non-Nucleoside
RTIs (NNRTIs)
Entry Inhibitors
Maraviroc
Enfuviritide
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
Tenofir Disoproxil
•Competitive
inhibitors
•No effect on host
enzymes
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
Nevirapine
Delavirdine
•Noncompetitive inhibitors
•Only active against HIV-1
•Easily vulnerable to resistance
Efavirenz
Closer Look: Efavirenz
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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
Indinavir
Atazanavir
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
 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)
http://aids.about.com/od/hivmedicationfactsheets/a/drugcost.htm
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. 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.