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Menlo Park, CA, United States

Nucleic acids analogues, i.e., oligonucleotide N3′→P5′ phosphoramidates and N3′→P5′ thiophosphoramidates, containing 3′-amino-3′-deoxy nucleosides with various 2′-substituents were synthesized and extensively studied. These compounds resist nuclease hydrolysis and form stable duplexes with complementary native phosphodiester DNA and, particularly, RNA strands. An increase in duplexes' melting temperature, ΔTm, relative to their phosphodiester counterparts, reaches 2.2-4.0° per modified nucleoside. 2′-OH- (RNA-like), 2′-O-Me-, and 2′-ribo-F-nucleoside substitutions result in the highest degree of duplex stabilization. Moreover, under close to physiological salt and pH conditions, the 2′-deoxy- and 2′-fluoro-phosphoramidate compounds form extremely stable triple-stranded complexes with either single- or double-stranded phosphodiester DNA oligonucleotides. Melting temperature, T m, of these triplexes exceeds Tm values for the isosequential phosphodiester counterparts by up to 35°. 2′-Deoxy- N3′→P5′ phosphoramidates adopt RNA-like C3′-endo or N-type nucleoside sugar-ring conformations and hence can be used as stable RNA mimetics. Duplexes formed by 2′-deoxy phosphoramidates with complementary RNA strands are not substrates for RNase H-mediated cleavage in vitro. Oligonucleotide phosphoramidates and especially thio-phosphoramidates conjugated with lipid groups are cell-permeable and demonstrate high biological target specific activity in vitro. In vivo, these compounds show good bioavailability and efficient biodistribution to all major organs, while exerting acceptable toxicity at therapeutically relevant doses. Short oligonucleotide N3′→P5′ thio-phosphoramidate conjugated to 5′-palmitoyl group, designated as GRN163L (Imetelstat), was recently introduced as a potent human telomerase inhibitor. GRN163L is not an antisense agent; it is a direct competitive inhibitor of human telomerase, which directly binds to the active site of the enzyme and thus inhibits its activity. This compound is currently in multiple Phase-I and Phase-I/II clinical trials as potential broad-spectrum anticancer agent. © 2010 Verlag Helvetica Chimica Acta AG.


Oligonucleotides with a novel sugar-phosphate backbone containing at least one 2-arabino-fluoronucleoside and an internucleoside 3-NHP(O)(OR)O-5 linkage, where R is a positively charged counter ion or hydrogen, and methods of synthesizing and using the inventive oligonucleotides are provided. The inventive phosphoramidate 2-arabino-fluorooligonucleotides have a high RNA binding affinity to complementary nucleic acids and are base and acid stable.


Patent
Geron | Date: 2015-05-22

Compounds comprising an oligonucleotide moiety covalently linked to a lipid moiety are disclosed. The oligonucleotide moiety comprises a sequence that is complementary to the RNA component of human telomerase. The compounds inhibit telomerase activity in cells with a high potency and have superior cellular uptake characteristics.


Patent
Geron | Date: 2015-05-22

Compounds comprising an oligonucleotide moiety covalently linked to a lipid moiety are disclosed. The oligonucleotide moiety comprises a sequence that is complementary to the RNA component of human telomerase. The compounds inhibit telomerase activity in cells with a high potency and have superior cellular uptake characteristics.


This invention relates to antisense oligonucleotides comprising at least one N3P5 phosphorodiamidate linkage (NPN) in the backbone as well as methods for using the same. The antisense oligonucleotides can effectively prevent or decrease protein expression.

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