Oligonucleotide end caps

Patent metadata

Field	Value
Publication number	US-9512164-B2
Application number	US-201013382353-A
Country	US
Kind code	B2
Filing date	Jul 7, 2010
Priority date	Jul 7, 2009
Publication date	Dec 6, 2016
Grant date	Dec 6, 2016

Abstract

Modified nucleic acids are described herein, including pharmaceutical compositions comprising the modified nucleic acids, and methods of using the modified nucleic acids.

First claim

We claim:

1. An oligonucleotide comprising a nucleosidic end cap represented by formula (Ib) or formula (IIb):

wherein:
J is an ether, sulfide, amino, ester, sulfonamide, amide, urea, carbamate, or a phosphorus-containing linkage;
K is independently O, S, NR′, or optionally substituted alkyl;
R′ is hydrogen, acyl, or unsubstituted or substituted aliphatic;
B 1 is independently a natural or modified nucleobase;
X 10 is H, OH, OM, SH, SM, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkylamino, or optionally substituted dialkylamino, where M represents independently for each occurrence an alkali metal or a transition metal with an overall charge of +1;
Z 10 is O, S, or NR′;
R, R 1 , R 2 , and R 3 are each independently H, OH, SH, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkylamino, or optionally substituted dialkylamino;
R 4 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or optionally substituted sulfonamide; and
s is an integer from 0-7.

2. The oligonucleotide of claim 1 , wherein the nucleosidic end cap is represented by formula (Ic) or formula (IIc):

wherein:
B 1 is a natural or modified nucleobase;
R is H, OH, OMe, F, or O(CH 2 ) n (Z)(CH 2 ) m —H, where n is 1-20, m is 0-20, and Z is O or S;
X 10 is H, OH, OM, SH, SM, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkylamino, or optionally substituted dialkylamino, where M represents independently for each occurrence an alkali metal or a transition metal with an overall charge of +1;
Z 10 is O, S, or NR′, where R′ is hydrogen, acyl, or unsubstituted or substituted aliphatic;
R 1 , R 2 and R 3 are each independently H, F, hydroxyl, alkoxy, amino, alkylamimo, or dialkylamino; and
R 4 is hydrogen, C 1 -C 32 alkyl, —C(X)—(CH 2 ) n —H, —C(X 1 )Y 1 —(CH 2 ) n —H, —C(X 1 )N(R b )—(CH 2 ) n —H, —(CH 2 ) n —NR b R c , —C(X 1 )—(CH 2 ) n —NR b R c , —C(X 1 )Y 1 —(CH 2 ) n —NR b R c , —C(X 1 )N(R b )—(CH 2 ) n —NR b R c , —(CH 2 ) n —N(R b )—C(═NR b )—NR b R c , —C(X 1 )—(CH 2 ) n —N(R b )—C(═NR b )—NR b R c , —C(X 1 )Y 1 —(CH 2 ) n —N(R b )—C(═NR b )—NR b R c or —C(X 1 )N(R b )—(CH 2 ) n —N(R b )—C(═NR b )—NR b R c , where n is 1-20; m is 0-20; X 1 is O or S; Y 1 is absent, O, or N(R b ), and each R b and R c is independently hydrogen or C 1 -C 32 alkyl.

3. An oligonucleotide comprising a nucleosidic end cap represented by formula (Id) or formula (IId):

wherein:
B 1 is a natural or modified nucleobase;
R is H, OH, OMe, F, or O(CH 2 ) n (Z)(CH 2 ) m —H, where n is 1-20, m is 0-20, and Z is O or S;
X and X 10 are each independently H, OH, OM, SH, SM, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkylamino, or optionally substituted dialkylamino, where M represents independently for each occurrence an alkali metal or a transition metal with an overall charge of +1;
Z 10 is independently O, S, or NR′;
R′ is hydrogen, acyl, unsubstituted or substituted aliphatic;
R 1 , R 2 and R 3 are each independently H, F, hydroxyl, alkoxy, amino, alkylamimo, or dialkylamino; and
R 4 is hydrogen, C 1 -C 32 alkyl, —C(X)—(CH 2 ) n —H, —C(X 1 )Y 1 (CH 2 ) n —H, —C(X 1 )N(R b )—(CH 2 ) n —H, —(CH 2 ) n —NR b R c , —C(X 1 )—(CH 2 ) n —NR b R c , —C(X 1 )Y 1 (CH 2 ) n —NR b R c , —C(X 1 )N(R b )—(CH 2 ) n —NR b R c , —(CH 2 ) n —N(R b )—C(═NR b )—NR b R c , —C(X 1 )—(CH 2 ) n —N(R b )—C(═NR b )—NR b R c , —C(X 1 )Y 1 —(CH 2 ) n —N(R b )—C(═NR b )—NR b R c or —C(X 1 )N(R b )—(CH 2 ) n —N(R b )—C(═NR b )—NR b R c , where n is 1-20; m is 0-20; X 1 is O or S; Y 1 is absent, O, or N(R b ), and each R b and R c is independently hydrogen or C 1 -C 32 alkyl.

4. An oligonucleotide comprising a nucleosidic end cap represented by formula (IIIc) or formula (IIId):

wherein:
B 1 is independently a natural or modified nucleobase;
X 10 is independently H, OH, OM, SH, SM, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkylamino, or optionally substituted dialkylamino, where M represents independently for each occurrence an alkali metal or a transition metal with an overall charge of +1;
Z 10 is independently O, S, or NR′;
R′ is hydrogen, acyl, or unsubstituted or substituted aliphatic;
R, R 2 and R 3 are each independently H, OH, SH, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkylamino, or optionally substituted dialkylamino; and
R 4 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or optionally substituted sulfonamide.

5. An oligonucleotide comprising a nucleosidic end cap represented by formula (IIIe) or formula (IIIf):

wherein:
B 1 is a natural or modified nucleobase;
X 10 is independently H, OH, OM, SH, SM, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkylamino, or optionally substituted dialkylamino, where M represents independently for each occurrence an alkali metal or a transition metal with an overall charge of +1;
Z 10 is independently O, S, or NR′
R′ is hydrogen, acyl, or unsubstituted or substituted aliphatic;
R, R 2 , and R 3 are each independently H, OH, SH, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkylamino, or optionally substituted dialkylamino;
R 4 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or optionally substituted sulfonamide.

6. The oligonucleotide of claim 1 , wherein said oligonucleotide is single-stranded siRNA.

7. The oligonucleotide of claim 1 , wherein said oligonucleotide is double-stranded siRNA.

8. The oligonucleotide of claim 3 , wherein said oligonucleotide is single-stranded siRNA.

9. The oligonucleotide of claim 3 , wherein said oligonucleotide is double-stranded siRNA.

10. The oligonucleotide of claim 4 , wherein said oligonucleotide is single-stranded siRNA.

11. The oligonucleotide of claim 4 , wherein said oligonucleotide is double-stranded siRNA.

12. The oligonucleotide of claim 5 , wherein said oligonucleotide is single-stranded siRNA.

13. The oligonucleotide of claim 5 , wherein said oligonucleotide is double-stranded siRNA.

Assignees

• Manoharan Muthiah
• Rajeev Kallanthottathil G
• Alnylam Pharmaceuticals Inc

Inventors

• Manoharan Muthiah
• Rajeev Kallanthottathil G

Classifications

• C12N15/115

  Aptamers, i.e. nucleic acids binding a target molecule specifically and with high affinity without hybridising therewith {; Nucleic acids binding to non-nucleic acids, e.g. aptamers} · CPC title

• C12N2310/31

  of the backbone · CPC title

• C12N2310/344

  Position-specific modifications, e.g. on every purine, at the 3'-end · CPC title

• C12N15/113 Primary

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title

• C07H21/04 Primary

  with deoxyribosyl as saccharide radical · CPC title