Chemical modifications of small interfering rna with minimal fluorine content

An oligonucleotide comprising:

• a sense strand comprising 17-36 nucleotides, wherein the sense strand has a first region (R1) and a second region (R2), wherein the second region (R2) of the sense strand comprises a first subregion (S1), a second subregion (S2) and a tetraloop (L) or triloop (triL) that joins the first and second regions, wherein the first and second subregions form a second duplex (D2);
• an antisense strand comprising 20-22 nucleotides, wherein the antisense strand includes at least 1 single-stranded nucleotide at its 3′-terminus, wherein the sugar moiety of the nucleotide at position 5 of the antisense strand is modified with a 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand is modified with a modification selected from 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-fluoro (2′-F), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), or 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA), and wherein the sense strand and antisense strand are separate strands;
• and
• a first duplex (D1) formed by the first region of the sense strand and the antisense strand, wherein the first duplex has a length of 12-20 base pairs and has 7-10 nucleotides that are modified at the 2′-position of the sugar moiety with 2′-F.

An oligonucleotide comprising:

• a sense strand comprising 17-36 nucleotides, wherein the sense strand has a first region (R1) and a second region (R2), wherein the second region (R2) of the sense strand comprises a first subregion (S1), a second subregion (S2) and a tetraloop (L) or triloop (triL) that joins the first and second regions, wherein the first and second subregions form a second duplex (D2);
• an antisense strand comprising 20-22 nucleotides, wherein the antisense strand includes at least 1 single-stranded nucleotide at its 3′-terminus, wherein the sugar moiety of the nucleotide at position 5 of the antisense strand is modified with a 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand is modified with a modification selected 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-fluoro (2′-F), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), or 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA), and wherein the sense strand and antisense strand are separate strands;
• and
• a first duplex (D1) formed by the first region of the sense strand and the antisense strand, wherein the first duplex has a length of 12-20 base pairs and has 10 nucleotides that are modified at the 2′-position of the sugar moiety with 2′-F.