An Overview of HIV Drugs
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Transcript An Overview of HIV Drugs
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
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)
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
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.