First novel phosphonocarboxylate DNA modifications in 20 years demonstrate all of the chemical and biochemical properties desired for DNA therapeutics
MetaSense Technologies has announced the publication of a set of two new DNA analogues in the prestigious The Journal of the American Chemical Society (125 (4), 940-950, 2003).
These novel DNA modifications, phosphonocarboxylates, are the first in 20 years to demonstrate all of the chemical and biochemical properties desired for DNA therapeutics.
Since the introduction of antisense technology almost two decades ago, antisense researchers have been waiting for new DNA analogues to fill their 'wish list' of desirable properties.
MetaSense says that, with this announcement, that wait has ended.
Biochemically, these new DNA analogues were shown to hybridise to complementary DNA and RNA, were RNaseH active, and highly nuclease resistant. Chemically, these analogs were prepared from the naturally occurring 2'-deoxynucleoside products, and a novel phosphorus reagent: making them simple and cost effective to manufacture on a large scale.
The publication was jointly submitted by MetaSense Technologies and the laboratory of Marvin Caruthers from the University of Colorado, department of chemistry and biochemistry.
"The promise of these analogues is very exciting, but our initial goal is to get these new tools into the hands of researchers quickly to see if they can satisfy that promise" said Dirk Dellinger, president of MetaSense Technologies, the corporation exclusively licensed to sell the reagents into the research markets.
"As we have talked to the research community it became obvious how hungry the field is for new and effective chemistry.
On the other hand, there is also a lot of cynicism as a result of 15 years of marginally effective medicinal chemistry approaches to making DNA analogues.
Those two points of view have driven our business strategy, and we can confidently say that the toolbox of the antisense researcher just got a lot bigger," he concluded.
"The key was in developing good phosphorus chemistry in combination with sound organic chemical principles that result in desired properties and behaviors," stated James Lindberg, chief technology officer for MetaSense.
"Like phosphorothioates, phosphonocarboxylates have been known as effective mimics of phosphate for almost a hundred years, but to date the coupling and deprotection chemistries used with these molecules made it impossible to make anything more than monomers and dimers of a single base.
The ability to quantitatively couple phosphonocarboxylates to any biological molecule has broadly sweeping implications beyond DNA therapeutics (antisense, RNAi, or gene therapy), and into phosphopeptides or small molecule therapeutics.
Although I can't predict the future, I can't wait to see where this chemistry leads our scientific community," he remarked.
