Structural compatibility of novel nucleotide modifications with shortened linkages designed for antigene/antisense therapy

Abstract

AbstractThe impact of isopolar shortened internucleotide linkage modification on the hybridization properties of potential antisense or antigene oligonucleotides was studied by using a model molecular system consisting of polyuridylic acid (PolyU) and analogs of diadenosine monophosphate with the modified linkage. Raman spectra of mixed aqueous solutions were measured at various temperatures and compositions of the mixtures for four types of modified linkage and natural ApA (3′–5′) as a reference. Analysis of the spectral sets provided amounts of formed complexes and their Raman spectra. It has been found that as in the case of ApA (3′–5′), the studied ApA analogs form with PolyU triplex‐like complexes containing a central pseudo‐chain of closely arranged adenosine dimers. In the case of S‐ and R‐configured 2′–5′ and 3′–5′ ApCOH A analogs, respectively, the amounts of complexes formed even exceed the ApA. This hybridization effectiveness is reached, however, by a more feasible prolongation of the pseudo‐chain, while the stability constant for the initiation step is significantly lower. Raman spectra of the complexes showed that for both of the above analogs the structural compatibility with the natural nucleic acid chain is decreased, because of the distorted position of one adenine residue. This distortion influences the Watson–Crick hydrogen bonds. The two types of linkages may be suitable just for construction of longer antigene or antisense oligonucleotides with alternating lengthened and shortened linkages. There is, however, a warning of possible decreased binding specificity. Copyright © 2004 John Wiley & Sons, Ltd.