Namir Sioufi

Improving antisense oligonucleotide binding to human serum albumin: Dramatic effect of ibuprofen conjugation

The interaction of antisense oligonucleotides with serum and cellular proteins determines their pharmacokinetic (transport to and distribution in target tissues) and pharmacodynamic (binding to the mRNA target) properties and hence their eventual pharmacology. In general, binding of drugs to serum albumin, 2-macroglobulin, immunoglobulins, and lipoproteins in the bloodstream governs their transport and tissue distribution. The first generation antisense compounds, 2 -deoxyphosphorothioate oligonucleotides (containing P S linkages, where R H and X S in Scheme 1), bind rapidly to serum and cellular

Activity of siRNAs with 2-thio-2'-O-methyluridine modification in mammalian cells.

In a search to identify chemical modifications to improve the properties of siRNA, we have investigated the effect of the 2 ′-O-methyl-2-thiouridine modification on the biological activity of siRNA. Our results indicate that judicious placement of 2 ′-O-methyl-2-thiouridine residues could lead to modified siRNA with activity in mammalian cells.

Synthesis of 2′-O-[2-[(N,N-dialkylamino)oxy]ethyl]-modified oligonucleotides: hybridization affinity, resistance to nuclease, and protein binding characteristics

Abstract Synthesis of a series of 2′-O-[2-[(N,N-dialkylamino)oxy]ethyl]-modified 5-methyluridine nucleoside phosphoramidites and solid supports are described. Using these monomers, modified oligonucleotides containing phosphodiester linkages were synthesized in high yields. These modified oligonucleotides showed enhanced binding affinity to the complementary RNA (and not to DNA) and excellent nuclease stability with t1/2>24 h. The human serum albumin binding properties of modified oligonucleotides have been evaluated to assess their transport and toxicity properties.