Nucleic acid derivatives

#The present invention relates to nucleotide analogs and their derived oligonucleotide analogs, methods of synthesizing both and the use of the oligonucleotide analogs in research, diagnosis and medical applications, e.g., for antisense therapy.

#An antisense oligonucleotide (e.g., antisense oligodeoxyribonucleotide) tray bind its target nucleic acid either by Watson-Crick base pairing or Hoogsteen and anti-Hoogsteen base pairing. To this effect see, Thuong and Helene (1993) Sequence specific recognition and modification of double helical DNA by oligonucleotides Angev. Chem. Int. Ed, Engl. 32:666. According to the Watson-Crick base pairing, heterocyclic bases of the antisense oligonucleotide form hydrogen bonds with the heterocyclic bases of target single-stranded nucleic acids (RNA or single-stranded DNA), whereas according to the Hoogsteen base pairing, the heterocyclic bases of the target nucleic acid are double-stranded DNA, wherein a third strand is accommodated in the major groove of the B-form DNA duplex by Hoogsteen and anti-Hoogsteen base pairing to form a triplex structure.

#According to both the Watson-Crick and the Hoogsteen base pairing models, antisense oligonucleotides have the potential to regulate gene expression and to disrupt the essential functions of the nucleic acids. Therefore, antisense oligonucleotides have possible uses in modulating a wide range of diseases.

#The invention is herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only, and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how the several forms of the invention may be embodied in practice.

#In the drawings:

#FIGS. 1a-b depict the eleven atoms separating nucleobases on (a) native DNA (FIG. 1a) and (b) an oligonucleotide compound having a polyether backbone according to a preferred embodiment of the present invention (FIG. 1b);

#The present invention is of oligomeric compounds which can be used as oligonucleotide analogs that bind to complementary DNA and RNA sequences. Specifically, the oligomeric compounds of the present invention include naturally occurring nucleobases (i.e., native nucleobase, e.g., A, C, G, T, U) or other nucleobase binding groups (i.e., a moiety which is not a native nucleobase, yet as native nucleobases may form hydrogen bonds with nucleobases in a way similar to native nucleobases, e.g., inosine, thiouracil, bromothymine, azaguanines, azaadenines, 5-methylcytosine etc., also referred herein as nucleobase analog) covalently bound to a backbone, which can be used as oligonucleotide analogs in research, diagnosis and in a variety of medical applications such as, but not limited to, antisense therapy. The oligonucleotide analogs of the present invention include cyclic moieties that enhance the formation of stable hybrids thereof with natural nucleic acids by providing the oligonucleotide analog with a rigidity that is compatible with the structure of natural nucleic acids upon pairing. The oligonucleotide analogs of the present invention are easily and efficiently synthesized and are further characterized by the other criteria for selecting antisense oligonucleotide analogs listed in the Background section hereinabove, including, but not limited to, (i) ease of synthetic procedure and proven synthetic efficiency and (ii) a rigidity that is compatible with the structure of natural nucleic acids, and which is further characterized by properties common to the above described polyether nucleic acids, such as (i) sufficient specificity in binding its target sequence; (ii) solubility in water: (iii) stability against intra- and extracellular nucleases; (iv) capability of penetrating through the cell membrane; and (v) when used to treat an organism, low toxicity, properties collectively rendering the polynucleotide analog of the present invention highly suitable as an antisense therapeutic drug.

#The synthesis, structure and mode of operation of the nucleotide analogs and the oligonucleotide antisense analogs according to the present invention may be better understood with reference to the drawings and accompanying descriptions.

#Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangement of the components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.