Oligonucleotides as drugs - ATDBio - Oligo synthesis …

 Induced cross-linking reactions to target genes using modified oligonucleotides

Patent US5571902 - Synthesis of oligonucleotides - …

A directed approach to the delivery of therapeutic oligonucleotides specifically to the liver has been to target the asialoglycoprotein receptor (ASGPR) using a suitable glycoconjugate. Indeed, ASGPR is the ideal target for delivery of therapeutic oligonucleotides to the liver since it combines tissue specificity, high expression levels and rapid internalization and turnover. The use of oligonucleotide glycoconjugates has led to significant advances in therapeutic delivery as evidenced by the work of Alnylam Pharmaceuticals and Ionis Pharmaceuticals using multivalent N-acetylgalactosamine (GalNAc) oligonucleotide conjugates.

Formation of N-branched oligonucleotides as by-products in solid-phase oligonucleotide synthesis

Phosphorothioate Bonds - Integrated DNA …

Solid-phase oligodeoxynucleotide synthesis has become a routine procedure in most molecular-biology laboratories. The reagents for the synthesis of unmodified oligomers have been available for several years, and novel commercially available reagents that permit the introduction of useful analogs into DNA are offered with increasing frequency. Solid-phase RNA synthesis is also becoming accessible to the molecular-biology community. If a suitable protected derivative is available, solid-phase synthesis is usually the preferred method of incorporating a nonstandard residue into an oligomer. However, there are still situations in which it is advantageous, or even essential, to approach the synthesis of modified oligonucleotides in a different way, namely by derivatizing unprotected oligonucleotides or their analogs.

Solid-Phase Synthesis of Oligodeoxyribonucleotides without Base Protection Utilizing O-Selective Reaction of Oxazaphospholidine Derivatives

Over a dozen antisense oligonucleotide drugs are undergoing human clinical trials for the treatment of viral infections, cancers, and a range of inflammatory disorders (Table 1). One of these was recently the first antisense oligonucleotide to demonstrate clinical safety and efficacy in pivotal Phase III clinical trials, in this case for the treatment of cytomegalovirus retinitis (Sanghvi et al., 1998). A dozen more antisense oligonucleotides have demonstrated pre-clinical efficacy (Crooke, 1998) and are under consideration for clinical development. In addition, use of antisense gene expression modulation to produce well-defined pharmacological effects is now a routine procedure (Akhtar et al., 1997). Automation of synthesis and ready access to required raw materials are two key reasons for the tumultuous growth in this area of research and development. Methods that allow preparation of a large number of pure oligonucleotides at reasonable cost expedite not only antisense drug discovery, but also open the door to manufacture of these drugs for market and the ultimate goal of delivery to patients. This chapter focuses on advances made in oligonucleotide process chemistry, the introduction and use of new reagents, and purification and analysis of antisense oligonucleotides.

Intracellular delivery of an antisense oligonucleotide via endocytosis of a G protein-coupled receptor


Synthesis of oligonucleotides on a soluble ..

72. Decristoforo C, Knopp R, von Guggenberg E, Rupprich M, Dreger T, Hess A. . A fully automated synthesis for the preparation of 68Ga-labelled peptides. 2007;28:870-5

Sequence analysis of phosphorothioate oligonucleotides via matrix ..

The most common and commercially available BFC comprise esters (-nitrophenyl, pentafluorophenyl, -hydroxysuccinimide, sulfo--hydroxysuccinimide), isothiocyanates, maleimides, hydrazides, α-haloamides for the reaction with nucleophilic functional groups (-NH2, -SH, -OH) of vector molecules and formation of amide, urea, thiourea, Schiff-base, or thioester bond []. Methods have been developed for the conjugation with peptides by solid-phase peptide synthesis (SPPS) resulting in defined position and number of chelate moieties. The outcome of the conjugation in solution wherein peptides and proteins comprise several reactive sites is very often a mixture of bioconjugate molecules with various content of the chelator. Such heterogeneity may cause the interpretation ambiguity of the performance of such imaging agents. Regioselective conjugation to antibodies was achieved by enzymatic reaction with lysine and glutamine residues using bacterial and human tissue transglutaminase as catalysts [].

Synthesis of Phosphorothioate Oligonucleotides …

We review nucleotide modifications, such as those to phosphate and sugar moieties that increase nuclease resistance or the range of activities possible, as well as whole nucleobase replacement that results in selective pairing and the creation of unnatural base pairs. Both in vitro and in vivo examples are discussed, including efforts to create semi-synthetic organisms with altered or expanded genetic alphabets.

Phosphorothioate oligonucleotides are synthesized by the ..

HBO was synthesized and incorporated into DNA oligonucleotides and each oligonucleotide was hybridized to a complementary oligonucleotide containing an abasic site at the position opposite HBO. Analysis of steady state emission spectra of the oligonucleotides indicates that the DNA environment selectively stabilizes the proton-transfer product tautomer of HBO, suggesting that flanking bases may be strongly coupled electronically.