Oligonucleotides with specific sequences are, in principle, useful medicinally
and as tools for biological research in part because of their ability to inhibit
the synthesis of a specific protein in living cells. This inhibition may occur
by at least two mechanisms: antisense, and RNA interference. In each case,
the exogenous oligonucleotides results in ablation of the messenger RNA, thus
preventing its translation into protein. However, the therapeutic use of oligonucleotides
has been limited by poor pharmacology (it is difficult to get DNA or RNA into cells
in multi-cellular organisms) and by their degradation by endogenous nucleases.
To alleviate both of these problems, a large amount of research has been devoted
to making modified oligonucleotides that retain their useful properties but that
are able to enter cells and survive nucleases. Often this research has focused
on unnatural backbone structures. However, while analogues with these virtues
have been prepared, their utility has been limited by the difficulty in their synthesis.
A template-directed strategy for the synthesis of unnatural oligonucleotides.
We are involved in the design of new synthetic methods potentially useful for the preparation
of modified oligonucleotides. Our strategy is to use a template-directed synthesis of such
materials in which a readily available normal DNA template is used to prepare a complementary
oligonucleotide, but with a modified backbone. This approach could greatly enhance the availability
of the unnatural oligonucleotides with potential value as antisense therapeutics or RNA interference agents.
I. Tamm, B. Dorken, and G. Hartmann Lancet 2001, 358 (9280), 489-497.
M. F. Taylor Drug Discov. Today 2001, 6 (15), S97-S101