Antisense Oligonucleotides as Potential Drugs
407
O
O
O
B
O
O
B
P
O
S
O
Sp-diastereomer
O
O
O
B
O
O
B
P
S
O
O
Rp-diastereomer
Phosphorothioates
O
O
B
N3
′ →
P5
Phosphoramidates
O
O
O
B
P
O
O
LNA
O
Alkyl phosphonates
(mixture of isomers)
N
O
B
P
O
N
O
N
HN
N
HN
O
O
O
B
Morpholino
PNA
Structures for antisense application
N
O
B
O
NH
O
B
P
O
O
O
O
O
B
O
O
O
B
P
CH
3
O
O
O
O
B
O
O
O
B
P
O
O
O
O CH
2
CH
2
OCH
3
(or S
)
2
-
O
-Methoxyethyl
O
B
cellular uptake, and thus constructing
ODNs with a neutral backbone was at-
tempted. Representatives for such ana-
logues are the methylphosphonates in
which the negatively charged phosphate
oxygen is replaced by a neutral methyl
group. These analogues have been used
very early for antisense inhibition of gene
expression. They are available through
automated oligonucleotide synthesis us-
ing methylphosphonamidites as synthons.
The methylphosphonate linkage is highly
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