Phosphorothioate oligonucleotides protein interactions

Phosphorothioate oligonucleotides can interact with nucleic acid binding proteins such as transcription factors and single-strand nu-cldc acid binding proteins. However, very little is known about these binding events. Additionally, it has been reported that phos-phorothioates bind to an 80-kDa membrane protein that was suggested to be involved in cellular uptake processes (87). However, again, little is known about the affinities, sequences, or structure specificities of these putative interactions. More recently, interactions with 30- and 46-kDa surface proteins in T15 mouse fibroblasts were reported (170). 

In conclusion, phosphorothioate oligonucleotides may interact with a wide range of proteins through several types of mechanisms. These interactions may influence the pharmacokinetic, pharmacologic, and toxicologic properties of these molecules. They may also complicate studies on the mechanism of action of these drugs, and may obscure an antisense activity. For example, phosphorothio-... 

Binding and Effects of Binding to Non-nucleic Acid Targets. Phosphorothioate oligonucleotides tend to bind to many proteins and those interactions are influenced by many factors. The effects of binding can influence cell uptake, distribution, metabolism, and excretion. They may induce non-antisense effects that can be mistakenly interpreted as... 

Phosphorothioate oligonucleotides bind to proteins. The interactions with proteins can be divided into nonspecific, sequence-specific, and structure-specific binding events, each of which may have different characteristics and effects. Nonspecific binding to a wide variety... 

Studies in humans have avoided peak plasma concentrations that would induce complement. However, it appears that monkeys are substantially more sensitive than humans to complement activation. A comparison of the effects on complement activation in human vs. monkey serum demonstrates a dramatic difference. In monkey serum, phosphorothioate oligodeoxynucleotides activate complement in a concentration-dependent fashion. It human serum, complement activation is actually inhibited at higher concentrations of oligonucleotide (169). This is thought to be attributable to the sensitivity of human serum to inhibition of complement activators. The mechanism of complement activation is currently believed to be attributable to an interaction with factor H (169). These effects can be reduced by chemical modifications and formulations that reduce plasma protein binding (169). 

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