Methylphosphonates are non-ionic nucleic acid analogs which contain nuclease resistant methylphosphonate linkages instead of the naturally occurring negatively charged phosphodiester bonds. These analogs are hydrophobic and are taken up by mammalian cells via passive diffusion. They have been found to be effective antisense reagents, capable of specifically controlling viral or cellular gene expression at the mRNA level.
These analogs form duplex hybrids with complementary nucleic acids by standard Watson-Crick base pairing interactions. Methylphosphonate/ RNA duplexes are not recognized by RNase H. This backbone has been proposed as an advantageous chemistry by Miller and T’so in the 80’s. The synthesis of methylphosphonate is now quite as easy as normal PO or PS oligos. But it remains that methylphosphonate uncharged backbone may induce some solubility problems.
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