Abstract
In this manuscript we describe for the first time mirror image catalytic nucleic acids (Spiegelzymes), which hydrolyze sequence specifically L-ribonucleic acid molecules. The mirror image nucleic acid ribozymes designed are based upon the known hammerhead ribozyme and DNAzyme structures that contain L-ribose or L-deoxyribose instead of the naturally occurring D-ribose or D-deoxyribose, respectively. Both Spiegelzymes show similar hydrolytic activities with the same L-RNA target molecules and they also exhibit extra ordinary stabilities when tested with three different human sera. In this respect they are very similar to Spiegelmers (mirror image aptamers), which we had previously developed and for which it has been shown that they are non-toxic and non-immunogenic. Since we are also able to demonstrate that the hammerhead and DNAzyme Spiegelzymes can also hydrolyze mirror image oligonucleotide sequences, like they occur in Spiegelmers, in vivo, it seems reasonable to assume that Spiegelzymes may in principle be used as an antidote against Spiegelmers. Since the Spiegelzymes contain the same building blocks as the Spiegelmers, it can be expected that they will have similar favorable biological characteristics concerning toxicity and immunogenety. In trying to understand the mechanism of action of the Spiegelzymes described in this study, we have initiated for the first time a model building system with L-nucleic acids. The models for L-hammerhead ribozyme and L-DNAzyme interaction with the same L-RNA target will be presented.
Highlights
Within the last 30 years it became apparent that natural nucleic acids may possess, besides their traditionally known functions in gene expression, an unforeseen structural and functional repertoire
Spiegelmers have found a number of interesting applications in biotechnology, and recently have even been entered into their first and second clinical testing phases as potential pharmaceutical drugs [7,8,14]. In this communication we describe for the first time mirror image catalytic nucleic acids, i.e., L-RNA hammerhead ribozymes and L-DNAzymes, constructed on the basis of the known D-RNA hammerhead ribozyme and D-DNAzyme [15,16,17,18,19,20,21,22,23,24] structures
After we had originally developed the mirror image aptamers called Spiegelmers [3,4], it was of interest to see, if we could develop mirror image nucleic acid enzymes (Spiegelzymes), cleaving sequence other mirror image nucleic acid targets
Summary
Within the last 30 years it became apparent that natural nucleic acids may possess, besides their traditionally known functions in gene expression, an unforeseen structural and functional repertoire. The problem of the instability of RNA molecules can partially be overcome by chemical modifications [5,6] Another very promising possibility of obtaining very stable RNA aptamers has been previously been demonstrated by us with the development of Spiegelmers, which are mirror image nucleic acid aptamers [3,4]. These Spiegelmers carry instead of the natural occurring D-ribose, L-ribose, and they are resistant to natural occurring nucleases. The resistance of Spiegelmers against nucleases has previously been reported [3,4,6] and will be shown in this communication
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