Oligonucleotides, chemically-modified oligonucleotides, and oligonucleotide-conjugate complexes for use in research, diagnostics, and/or therapeutics are described herein. In some embodiments, oligonucleotides comprising a stabilized phosphate moiety covalently attached to the 5′-terminal nucleoside
Oligonucleotides, chemically-modified oligonucleotides, and oligonucleotide-conjugate complexes for use in research, diagnostics, and/or therapeutics are described herein. In some embodiments, oligonucleotides comprising a stabilized phosphate moiety covalently attached to the 5′-terminal nucleoside are provided.
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1. A compound comprising an oligonucleotide consisting of 10-30 linked nucleosides and at least one conjugate group, wherein the 5′-terminal nucleoside of the oligonucleotide has Formula IV: wherein: T1 is wherein: Ra and Rc are each, independently, OH, SH, C1-C6 alkyl, substituted C1-C6 alkyl, C1
1. A compound comprising an oligonucleotide consisting of 10-30 linked nucleosides and at least one conjugate group, wherein the 5′-terminal nucleoside of the oligonucleotide has Formula IV: wherein: T1 is wherein: Ra and Rc are each, independently, OH, SH, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, amino or substituted amino; andRb is O or S;T2 is an internucleoside linking group linking the compound of Formula IV to the remainder of the oligonucleotide;Q1 and Q2 are each, independently, H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2-C6 alkynyl, C1-C6 alkoxy, substituted C1-C6 alkoxy or N(R3)(R4);each R3 and R4 is, independently, H, C1-C6 alkyl or substituted C1-C6 alkyl;Bx is a heterocyclic base moiety;G is H, OH, halogen, a conjugate group, or O—[C(R8)(R9)]n—[(C═O)m—X1]j—Z;each R8 and R9 is, independently, H, halogen, C1-C6 alkyl or substituted C1-C6 alkyl;X1 is O, S or N(E1);Z is H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2-C6 alkynyl or N(E2)(E3);E1, E2 and E3 are each, independently, H, C1-C6 alkyl or substituted C1-C6 alkyl;n is from 1 to about 6;m is 0 or 1;j is 0 or 1;each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ1, N(J1)(J2), ═NJ1, SJ1, N3, CN, OC(═X2)J1, OC(═X2)—N(J1)(J2) and C(═X2)N(J1)(J2);X2 is O, S or NJ3;each J1, J2 and J3 is, independently, H or C1-C6 alkyl; andprovided that when j is 1 then Z is other than halogen or N(E2)(E3). 2. The compound of claim 1, wherein the conjugate group is covalently attached to the oligonucleotide at a nucleoside at position 1, 2, 3, 4, 6, 7, 8, 9, 18, 19, 20, or 21 from the 5′-end of the oligonucleotide or at position 1, 2, 3, 12, 13, 4, 15, 17, 18, 19, 20, or 21 from the 3′-end of the oligonucleotide. 3. The compound of claim 2, wherein the conjugate group is covalently attached to any of the 1 to 4 5′-most terminal nucleosides of the oligonucleotide. 4. The compound of claim 2, wherein the conjugate group is covalently attached to the 5′-terminal nucleoside of the oligonucleotide. 5. The compound of claim 2, wherein the conjugate group is covalently attached to the 8th nucleoside from the 5′-terminal end of the oligonucleotide. 6. The compound of claim 2, wherein the conjugate group is covalently attached to the 6th nucleoside from the 5′-terminal end of the oligonucleotide. 7. The compound of claim 2, wherein the conjugate group comprises C20 alkyl. 8. The compound of claim 2, wherein the conjugate group comprises C16 alkyl. 9. The compound of claim 2, wherein the conjugate group comprises C10 alkyl. 10. The compound of claim 2, wherein the conjugate group comprises a steroid. 11. The compound of claim 2, wherein the conjugate group comprises cholesterol. 12. The compound of claim 2, wherein the conjugate group comprises a carbohydrate. 13. The compound of claim 2, wherein the conjugate group comprises N-acetylgalactosamine. 14. The compound of claim 2, wherein each nucleoside is a modified nucleoside. 15. The compound of claim 2, comprising at least one 2′-substituted nucleoside. 16. The compound of claim 2, wherein the compound is single-stranded. 17. The compound of claim 2, wherein each of the 6 to 9 3′-most terminal internucleoside linkages is a phosphorothioate linkage and each of the other internucleoside linkages is a phosphodiester linkage. 18. The compound of claim 2, wherein each of the 6 to 9 3′-most terminal internucleoside linkages is a phosphorothioate linkage and each of the other internucleoside linkages is a phosphodiester or a phosphorothioate linkage. 19. The compound of claim 2, wherein the conjugate group comprises C10 to C22 alkyl. 20. The compound of claim 2, wherein the conjugate group comprises C10 to C22 alkenyl. 21. The compound of claim 2, wherein the conjugate group comprises C22 alkyl.
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