Comment: The INN record for donidalorsen describes it as a prekallikrein synthesis reducer. It is an antisense oligonucleotide (ASO) from Ionis Pharmaceuticals (formerly IONIS-PKK-LRx or ISIS 721744) that targets prekallikrein mRNA. The ASO is conjugated to a three N-acetylgalactosamine (GalNAc) moieties to improve delivery to the site of prekallikrein production in hepatocytes [
2]. By silencing prekallikrein donidalorsen down-modulates the defective C1 inhibitor-prekallikrein-bradykinin pathway which promotes vasodilation, vascular permeability and dangerous episodes of tissue swelling that are characteristic of hereditary angioedema.
Full sequence as provided in the agent's INN record is: all-P-ambo-5'-O-(28-[(2-acetamido-2-deoxy-β-D-galactopyranosyl)oxy]-16,16-bis{[3-({6-[(2-acetamido-2-deoxy-β-D-galactopyranosyl)oxy]hex-yl}amino)-3-oxopropoxy]methyl}-1-hydroxy-1,10,14,21-tetraoxo-2,18-dioxa-9,15,22-triaza-1λ
5 -phosphaoctacosan-1-yl)-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')- 2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methylcytidylyl-(3'→5')-2'-O-(2-methoxyethyl)adenylyl-(3'→5')-2'-O-(2- methoxyethyl)-P-thioadenylyl-(3'→5')-2'-deoxy-P-thioguanylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxy-5-methyl-P-thiocytidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxy-5-methyl-P-thiocytidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxy-P-thioguanylyl- (3'→5')-2'-deoxy-P-thioguanylyl-(3'→5')-2'-deoxy-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)adenylyl-(3'→5')-2'-O-(2- methoxyethyl)adenylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P- thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)adenosine, but we have been unable to resolve this to a SMILES or HELM notation.
