Nucleic acid, pharmaceutical composition and conjugate containing nucleic acid, and use thereof

A siRNA capable of inhibiting the expression of HBV gene, comprising a sense strand and an antisense strand, wherein each nucleotide in the sense strand and the antisense strand is a modified nucleotide, wherein the sense strand and the antisense strand both comprise fluoro modified nucleotides and non-fluoro modified nucleotides;

• a “fluoro modified nucleotide” refers to a nucleotide formed by substituting the 2′-hydroxy of the ribose group of the nucleotide with a fluoro group, and a “non-fluoro modified nucleotide” refers to a nucleotide formed by substituting the 2′-hydroxy of the ribose group of the nucleotide with a non-fluoro group, or a nucleotide analogue;
• the sense strand comprises a nucleotide sequence 1;
• the antisense strand comprises a nucleotide sequence 2;
• the nucleotide sequence 1 and the nucleotide sequence 2 are at least partly reverse complementary to form a double-stranded region;
• wherein the nucleotide sequence 1 and the nucleotide sequence shown in SEQ ID NO:
• 1 have an equal length and no more than 3 nucleotide differences;
• and the nucleotide sequence 2 and the nucleotide sequence shown in SEQ ID NO:
• 2 have an equal length and no more than 3 nucleotide differences:
• (SEQ ID NO:
• 1)
• 5′-GAAAGUAUGUCAACGAAUZ-3′,
• (SEQ ID NO:
• 2)
• 5′-Z'AUUCGUUGACAUACUUUC-3′,
• wherein Z is U, Z′ is A;
• the nucleotide sequence 1 comprises a nucleotide ZA at the position corresponding to Z;
• the nucleotide sequence 2 comprises a nucleotide Z′B at the position corresponding to Z′;
• the nucleotide Z′B is the first nucleotide from 5′ terminal of the antisense strand;
• and
• the fluoro modified nucleotides are located within the nucleotide sequence 1 and the nucleotide sequence 2;
• the nucleotide sequence 1 comprises no more than 5 fluoro modified nucleotides, and in the direction from 5′ terminal to 3′ terminal, the nucleotides at positions 7, 8 and 9 of the nucleotide sequence 1 are fluoro modified nucleotides;
• the nucleotide sequence 2 comprises no more than 7 fluoro modified nucleotides and the nucleotides at positions 2, 6, 14 and 16 of the nucleotide sequence 2 are fluoro modified nucleotides.