Exiqon A/s

Santaris Pharma A/s

Jesper Wengel

Poul Sejer Nielsen

Troels Koch

Christoph Rosenbohm

Daniel Sejer Pedersen

Signe M Christensen

Mads Detlef Sørensen

Sakari Kauppinen

Jorgen Kjems

Mads Detlef Sorensen

The invention relates to a novel strategy for the synthesis of Locked Nucleic Acid derivatives, such as &#x3b1;--oxy-LNA, amino-LNA, &#x3b1;--amino-LNA, thio-LNA, &#x3b1;--thio-LNA, seleno-LNA and methylene LNA, which provides scalable high yielding reactions utilising intermediates that also can produce other LNA analogues such as oxy-LNA. Also, the compounds of the formula X are important intermediates that may be reacted with varieties of nucleophiles leading to a wide variety of LNA analogues. 

Synthesis of locked nucleic acid derivatives

The present invention is directed to pharmaceutical and therapeutic compositions which comprise RNA complexes comprising an antisense strand and a discontinued passenger strand capable of regulating gene expression. The use of a discontinued passenger strand reduces off target effects of the RNA complexes and also has other advantages.

Small internally segmented interfering RNA

The present invention relates to novel bicyclic and tricyclic nucleoside and nucleotide analogues as well as to oligonucleotides comprising such elements. The nucleotide analogues, LNAs (Locked Nucleoside Analogues), are able to provide valuable improvements to oligonucleotides with respect to affinity and specificity towards complementary RNA and DNA oligomers. The novel type of LNA modified oligonucleotides, as well as the LNAs as such, are useful in a wide range of diagnostic applications as well as therapeutic applications. Among these can be mentioned antisense applications, PCR applications, strand displacement oligomers, as substrates for nucleic acid polymerases, as nucleotide based drugs, etc. The present invention also relates to such applications.

Oligonucleotide analogues

Methods are described for the synthesis of Locked Nucleic Acid (LNA) derivatives using certain nitrogen-containing nucleophiles.

The invention relates to a novel strategy for the synthesis of Locked Nucleic Acid derivatives, such as &#x3b1;--oxy-LNA, amino-LNA, &#x3b1;--amino-LNA, thio-LNA, &#x3b1;--thio-LNA, seleno-LNA and methylene LNA, which provides scalable high yielding reactions utilizing intermediates that also can produce other LNA analogues such as oxy-LNA. Also, the compounds of the formula X are important intermediates that may be reacted with varieties of nucleophiles leading to a wide variety of LNA analogues. 

Based on the above and on the remarkable properties of the 2'-O,4&#x2032;-C-methylene bridged LNA monomers it was decided to synthesise oligonucleotides comprising one or more 2&#x2032;-O,4&#x2032;-C-methylene-&#x3b2;-D-xylofuranosyl nucleotide monomer(s) as the first stereoisomer of LNA modified oligonucleotides. Modelling clearly indicated the xylo-LNA monomers to be locked in an N-type furanose conformation. Whereas the parent 2&#x2032;-deoxy-&#x3b2;-D-xylofuranosyl nucleosides were shown to adopt mainly an N-type furanose conformation, the furanose ring of the 2&#x2032;-deoxy-&#x3b2;-D-xylofuranosyl monomers present in xylo-DNA were shown by conformational analysis and computer modelling to prefer an S-type conformation thereby minimising steric repulsion between the nucleobase and the 3&#x2032;-O-phopshate group (Seela, F.; W&#xf6;mer, Rosemeyer, H.1994, 77, 883). As no report on the hybridisation properties and binding mode of xylo-configurated oligonucleotides in an RNA context was believed to exist, it was the aim to synthesise 2&#x2032;-O,4&#x2032;-C-methylene-&#x3b2;-D-xylofuranosyl nucleotide monomer and to study the thermal stability of oligonucleotides comprising this monomer. The results showed that fully modified or almost fully modified Xylo-LNA is useful for high-affinity targeting of complementary nucleic acids. When taking into consideration the inverted stereochemistry at C-3&#x2032; this is a surprising fact. It is likely that Xylo-LNA monomers, in a sequence context of Xylo-DNA monomers, should have an affinity-increasing effect.

Xylo-LNA analogues

Modified LNA units are provided that comprises unique base groups. Desirable nucleobase and nucleosidic base substitutions can mediate universal hybridization when incorporated into nucleic acid strands. The novel LNA compounds may be used in a wide variety of applications, such as PCR primers, sequencing, synthesis of antisense oligonucleotides, diagnostics and the like.

LNA compositions and uses thereof

Provided are L-ribo bicyclic nucleotide compounds as well as syntheses of such compounds. The nucleoside compounds of the invention are useful in forming oligonucleotides that can produce nucleobase specific duplexes with complementary single stranded and double stranded nucleic acids.

L-ribo-LNA analogues

Novel oligomers, and synthesis thereof, comprising one or more bi-, tri, or polycyclic nucleoside analogues are disclosed herein. The nucleoside analogues have a 'locked' structure, termedockeducleosidenalogues (LNA). LNA's exhibit highly desirable and useful properties. LNA's are capable of forming nucleobase specific duplexes and triplexes with single and double stranded nucleic acids. These complexes exhibit higher thermostability than the corresponding complexes formed with normal nucleic acids. The properties of LNA's allow for a wide range of uses such as diagnostic agents and therapeutic agents in a mammal suffering from or susceptible to, various diseases.

Novel oligomers, and synthesis thereof, comprising one or more bi-, tri, or polycyclic nucleoside analogues are disclosed herein. The nucleoside analogues have a &ldquo;locked&rdquo; structure, termed Locked Nucleoside Analogues (LNA). LNA's exhibit highly desirable and useful properties. LNA's are capable of forming nucleobase specific duplexes and triplexes will single and double stranded nucleic acids. These complexes exhibit higher thermostability than the corresponding complexes formed with normal nucleic acids. The properties of LNA's allow for a wide range of uses such as diagnostic agents and therapeutic agents in a mammal suffering from or susceptible to, various diseases.

Novel oligomers, and synthesis thereof, comprising one or more bi-, tri, or polycyclic nucleoside analogues are disclosed herein. The nucleoside analogues have a &ldquo;locked&rdquo; structure, termed Locked Nucleoside Analogues (LNA). LNA's exhibit highly desirable and useful properties. LNA's are capable of forming nucleobase specific duplexes and triplexes with single and double stranded nucleic acids. These complexes exhibit higher thermostability than the corresponding complexes formed with normal nucleic acids. The properties of LNA's allow for a wide range of uses such as diagnostic agents and therapeutic agents in a mammal suffering from or susceptible to, various diseases.

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Odense S, Denmark

Jesper Wengel