066 CHAPTER 27 Nucleosides, Nucleotides, and Nucleic Acids
Notice that in the phosphoramidite method an oxidation is done each time a
monomer is added, whereas in the H-phosphonate method a single oxidation is carried
out after the entire strand has been synthesized.PROBLEM 27Propose a mechanism for removal of the DMTr protecting group by treatment with acid.27.17 Rational Drug Design
Certain diseases such as acquired immunodeficiency syndrome (AIDS) and herpes are
caused by retroviruses. The genetic information of a retrovirus is contained in its
RNA. The retrovirus uses the sequence of bases in RNA as a template to synthesize
DNA. It is called a retrovirus because its genetic information flows from RNA to DNA
instead of the more typical flow from DNA to RNA.
Drugs that interfere with the synthesis of DNA by retroviruses have been designed
and developed. If the retrovirus cannot synthesize DNA, it cannot take over the ge-
netic machinery of the cell to produce more retroviral RNA and retroviral proteins.
Designing drugs with particular structures to achieve specific purposes is called
rational drug design. AZT is perhaps the best known of the drugs designed to inter-
fere with retroviral DNA synthesis. AZT is taken up by the T lymphocytes, cells that
are particularly susceptible to human immunodeficiency virus (HIV), the retrovirus
that causes AIDS. Once in the cell, AZT is converted to AZT-triphosphate. The retro-
viral enzyme (reverse transcriptase) that catalyzes DNA formation from RNA binds
AZT-triphosphate more tightly than it binds dTTP. Therefore, AZT rather than T is
added to the growing DNA chain. Because AZT does not have a group, no ad-
ditional nucleotides can be added to the chain and DNA synthesis comes to a sudden
halt. Fortunately, the concentration of AZT required to affect reverse transcription is
too low to affect most cellular DNA replication. A newer drug, -dideoxyinosine
(ddI), has a similar mechanism of action. Rational drug design is further discussed in
Chapter 30.2 ¿,3¿3 ¿-OHphosphate
groupH-phosphonate
groupsolid supportOOOObase PrOObase PrPOOOOObase PrH PHsolid supportOOOObase PrOObase PrPOOOOObase Pr−O P−OI 2