Reactive oligonucleotide derivatives as gene-targeted biologically active compounds and affinity probes

Abstract

Development of efficient methods for synthesis of oligonucleotides and oligonucleotide analogs has opened up the possibility of designing a broad spectrum of affinity reagents for specific modification of nucleic acids and proteins. These affinity reagents are used for investigation of the topology of ribosomes and nucleic acid polymerases. Oligonucleotides and their analogs are already used for suppression of specific gene expression and for elucidation of the physiological role of their products. Oligonucleotide derivatives appear to offer considerable promise as potential gene-targeted drugs such as antivirals and specific inhibitors of oncogene expression.

Covalent cross-linking of duplex DNA using 4-thio-2'-deoxyuridine as a readily modifiable platform for introduction of reactive functionality into oligonucleotides

“…A number of workers have used the Grineva concept to effect covalent cross-linking or modification of DNA. Particularly pertinent examples include those of Vlassov using a 3′ or 5′-tethered N-(2-chloroethyl)arylamines (3)(4)(5), Summerton and Bartlett (6) with a tethered α-bromoketone, Matteucci (7) with an N,N-ethanocytosine, Dervan (8-10) with an α-haloacetamido group within a triple-helical complex, and Ohtsuka (11) and Tabone and co-workers (12) using an α-haloacetamide system within duplex DNA. These workers have achieved varying degrees of success in effecting covalent cross-linking, ranging from 1-2% to essentially quantitative.…”

Sequence and Structure Dependence of the Hybridization-Triggered Reaction of Oligonucleotides Bearing Conjugated Cyclopropapyrroloindole

“…ODNs bearing haloacetamides have limited application in cellular systems due to their inherent reactivity, both with themselves and with nontarget cellular nucleophiles prior to nucleic acid binding. The mustards offer advantages in reactivity due to their spontaneous activation, 8 but may still react at nontarget sites.…”

Site specific photo-crosslinking of single stranded oligonucleotides by a complementary sequence equipped with an internal photoactive probe

“…1,2 In nucleic acid studies, although simple oligonucleotide binding may not be sufficient to disrupt nucleic acid functions, inactivation will certainly occur if, after specific recognition, a modified oligonucleotide probe has the capacity to undergo irreversible covalent photo-crosslinking to its target. 3 In such probes, a photoactive label is usually introduced at their 5A-terminus, excepted for some examples with psoralens whose applications are specific of AT sites. 4 Herein, we have examined the photochemical behaviour towards their DNA and RNA targets of strictly complementary constructs having a photoactive nucleoside residue which can be easily placed at a defined position within the sequence.…”