Transcript Presentation_39

AZT = Azidothymidine (3’-azido-3’-deoxythymidine, Zidovudine)
Acts as inhibitor of intracellular enzyme known as reverse transcriptase, responsible
for utilizing viral RNA to generate a copy of DNA with appropriate code to generate
new virus.
Treatment of HIV
• When HIV replicates (makes new copies of itself) it
often makes mistakes.
• Taking two or more antiretrovirals at the same time
vastly reduces the rate at which resistance develops
• The term Highly Active Antiretroviral Therapy
(HAART) is used to describe a combination of three
or more anti-HIV drugs.
Treatment of HIV
• Current classes of antiretroviral drugs include:
– Nucleoside/Nucleotide Reverse Transcriptase
Inhibitors
– Non-Nucleoside Reverse Transcriptase Inhibitors
– Protease Inhibitors
– Fusion or Entry Inhibitors
– Integrase Inhibitors
Nucleoside/Nucleotide Reverse
Transcriptase Inhibitors
• These were the first type of drug available to treat
HIV infection in 1987.
• NRTIs (also known as nucleoside analogues or
nukes) interfere with the action of an HIV protein
called reverse transcriptase, which the virus
needs to make new copies of itself.
• NRTIs are sometimes called the "backbone" of
combination therapy because most regimens
contain at least two of these drugs.
Antiretroviral Agents Currently Available (generic name/Trade
name) Nucleoside Analogs (NRTI’s)
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zidovudine/Retrovir(AZT, ZDV)
didanosine/Videx, Videx EC (ddI)
zalcitabine/HIVID (ddC)
stavudine/Zerit (d4T)
lamivudine/Epivir (3TC)
abacavir/Ziagen (ABC)
Nucleoside Reverse Transcriptase Inhibitors
(NRTI’s)
Zidovudine/Retrovir
(AZT, ZDV)
didanosine/Videx, Videx
EC (ddI)
zalcitabine/HIVID (ddC)
The AZT works by interfering with reverse transcription, as shown in the LINK, but
must first be converted to the triphosphate
Link
Since phosphates are charged at neutral pH, and thus do not cross the cell membrane,
suitably protected phosphate derivatives might serve as ‘prodrugs’ which can be
hydrolytically cleaved once inside the cell.
Thus it was desired to prepare phosphate esters which would be rapidly chemically
hydrolyzed at neutral pH. Two types of phosphate esters were explored:
However, neither of these approaches worked, since the hydrolysis always stops at
the (negatively charged) phosphodiester level
The problem was solved by protecting the two phosphate esters differently, one as a phenyl
ester, and one as a benzyl ester, through use of a cyclic diester derivative of salicylic acid.
Note that the phenyl ester will be hydrolytically cleaved quickly, followed by slower
cleavage of the benzyl ester. However, the intermediate phenol can serve as a proton
donor, and, as a negatively charged phenolate anion, also serves to activate the leaving
of the phosphate in an Sn1 fashion.