Zerlasiran

Zerlasiran is a double-stranded small interfering RNA (siRNA) of 19 nucleotides in length for strand. Most of the ribonucleotides are chemically modified (mainly 2′-O-methyl or 2′-fluoro-2′-deoxy sugars, with some phosphorothioate linkages) to enhance stability and reduce immunogenicity. The drug is a duplex of these modified oligonucleotides. The sense strand is 5′-conjugated with a tri-antennary N-acetyl-D-galactosamine (GalNAc) cluster attached through a multi-arm phosphodiester linker, enabling targeted delivery to the liver.^[2]

Antisense strand:^[3]

• unmodified: UAGAUGACCAAGCUUGGCA
• modified: mA (ps) fI (ps) mA fA mC fI mC fI mG fI mC fC mA fI mU fA mC (ps) fC (ps) mG

where:

• "m" denotes 2'-O-methyl modification,
• "f" denotes 2'-fluoro modification,
• “ps” denotes a phosphorothioate linkage,
• “I” is likely for inosine or another modified base,

Sense strand:^[3]

• unmodified: UUGCCAAGCUUGGUCAUCU
• modified: [M]-mC mG mG mU mA mA fU fG fG mA mC mA mG mA mG mU mU (ps) mA (ps) mU

where: "[M]" is a triantennary N-acetylgalactosamine (GalNAc) ligand attached to the 5’ end for hepatic targeting. Other abbreviations follow the sense strand modifications as above.