Phosphorothioate antisense oligonucleotide-binding proteins (PS-ASO binding proteins) (PS-ASO binding proteins)

Phosphorothioate antisense oligonucleotide (PS-ASO) binding proteins are a heterogeneous class of proteins that interact with the phosphorothioate backbone of modified nucleic acid therapeutics. In the blood, albumin serves as the primary carrier, preventing rapid renal excretion and facilitating systemic distribution (Gaus et al., 2019, PMID: 31114618). Cellular entry is primarily driven by scavenger receptors, notably Stabilin-1 and Stabilin-2, which mediate endocytosis in the liver and other tissues (Crooke et al., 2017, PMID: 28332947). Within the cell, these oligonucleotides associate with various proteins such as nucleolin and p54nrb, which dictate their sub-cellular localization and availability for binding to target mRNA (Crooke et al., 2021, PMID: 33762737). While these interactions are critical for the pharmacological activity of ASOs, they can also trigger adverse effects, including complement system activation and transient thrombocytopenia. Understanding these protein-drug interactions is vital for optimizing the safety and efficacy of antisense therapies.

Other names

PS-ASO-binding proteinsOligonucleotide-binding proteinsASO-interacting proteinsPhosphorothioate-binding proteins

Phosphorothioate antisense oligonucleotides (PS-ASOs) interact with these proteins to facilitate their systemic transport, protect them from nuclease-mediated degradation, and mediate their cellular uptake and intracellular trafficking via receptor-mediated endocytosis.