Modified iRNA agents
AssigneeAlnylam Pharmaceuticals, Inc.
InventorsMuthiah Manoharan, Venkitasamy Kesavan, Kallanthottathil G. Rajeev
Life of this patent
Estimating the term…
Abstract
The invention relates to iRNA agents, which preferably include a monomer in which the ribose moiety has been replaced by a moiety other than ribose. The inclusion of such a monomer can allow for modulation of a property of the iRNA agent into which it is incorporated, e.g., by using the non-ribose moiety as a point to which a ligand or other entity, e.g., a lipophilic moiety. e.g., cholesterol, is directly, or indirectly, tethered. The invention also relates to methods of making and using such modified iRNA agents.
Claims48
An iRNA agent comprising a first strand and a second strand, wherein at least one subunit having a formula (I) is incorporated into at least one of said strands:
- wherein:
- X is N(CO)R7, NR7 or CH2;
- Y is NR8, O, S, CR9R10, or absent;
- Z is CR11R12 or absent;
- Each of R1, R2, R3, R4, R9, and R10 is, independently, H, ORa, ORb, (CH2)nORa, or (CH2)nORb, provided that at least one of R1, R2, R3, R4, R9, and R10 is ORa or ORb and that at least one of R1, R2, R3, R4, R9, and R10 is (CH2)nORa, or (CH2)nORb;
- Each of R5, R6, R11, and R12 is, independently, H, C1-C6 alkyl optionally substituted with 1-3 R13, or C(O)NHR7;
- or R5 and R11 together are C3-C8 cycloalkyl optionally substituted with R14;
- R7 is Rd;
- or C1-C20 alkyl substituted with NRcRd or NHC(O)Rd;
- R8 is C1-C6 alkyl;
- R13 is hydroxy, C1-C4 alkoxy, or halo;
- R14 is NRcR7;
- Ra is H or
- Rb is H or
- wherein the Strand in each occurrence is independently the first strand or second strand of the iRNA agent;
- each of A and C is, independently, O or S;
- and
- B is OH, O−, or
- Rc is H or C1-C6 alkyl;
- Rd is H or a ligand;
- and
- n is 1-4.
An iRNA agent delivery module of formula Y:
- wherein:
- A is an iRNA agent;
- W and Z are independently NH, O, or S;
- X and Y are independently S, Se, BH3−, C1-C6 alkyl, C6-C10 aryl, H, O, O−, alkoxy, or amino;
- R1 and R3 are each, independently, hydrogen or C1-C100 alkyl, optionally substituted with hydroxyl, amino, halo, phosphate or sulfate and/or may be optionally inserted with N, O, S, alkenyl or alkynyl;
- R2 is hydrogen or C1-C100 alkyl, optionally substituted with hydroxyl, amino, halo, phosphate or sulfate and/or may be optionally inserted with N, O, S, alkenyl or alkynyl;
- or, when n is 1, R2 may be taken together with R4 or R6 to form a ring of 5-12 atoms;
- R4 is hydrogen or C1-C100 alkyl, optionally substituted with hydroxyl, amino, halo, phosphate or sulfate and/or may be optionally inserted with N, O, S, alkenyl or alkynyl;
- or, when n is 1, R4 may be taken together with R2 or R5 to form a ring of 5-12 atoms;
- R5 is hydrogen or C1-C100 alkyl optionally substituted with hydroxyl, amino, halo, phosphate or sulfate and/or may be optionally inserted with N, O, S, alkenyl or alkynyl;
- or, when n is 1, R5 may be taken together with R4 to form a ring of 5-12 atoms;
- R6 is hydrogen or C1-C100 alkyl, optionally substituted with hydroxyl, amino, halo, phosphate or sulfate and/or may be optionally inserted with N, O, S, alkenyl or alkynyl, or, when n is 1, R6 may be taken together with R2 to form a ring of 6-10 atoms;
- R7 is hydrogen, C1-C100 alkyl, or C(O)(CH2)qC(O)NHR9;
- R9 is hydrogen, C1-C100 alkyl, C6-C10 aryl, or a solid support agent;
- n and q are each independently 1-100;
- and
- T is hydrogen or a functional group selected from the group consisting of a steroid, a carbohydrate, a fluorophore, an isotopically labelled moiety, a protein binding agent, a RGD peptide or a mimetic thereof, a folate, a vitamin B12, a biotin, a bisphosphonate, a polyglutamate, a polyaspartate, a multivalent mannose, a lactose, a galactose, a N-acetyl-galactosamine, a monoclonal antibody, a glycoprotein, a lectin, a melanotropin, a thyrotropin, and a combination thereof.
Dependencies are inferred from the claim text.