Sinteza in strukturne raziskave bioloških makromolekul (Slovene)

The programme is focused on two specific objectives. Ad 1) Synthetic modifications of carefully designed nonnatural building blocks for oligonucleotide synthesis targeted versus biological response, namely to block coded genetic messages as a basis for moust diseases. Ad 2) Structural studies of these novel moietis either in solution by NMR methods or by X-ray diffraction. We have found the firm idea on the improvement of the affinity of novel non-natural short oligonucleotides suitable for either antisense or antigene technologies to their targets. The novel building blocks mostly modified guanosines (aza, deaza, modified sugars, chiral carbocyclic sugar analogues and/or N7 and N9 positional isomers). The advantage in this approach is a selection and proper choice of the arrangements of hydrogen bond patterns. In addition, platinated building bloks of the unique so called ambigous nucleosides are proposed, aimed versus directed inter-strand cross-linking in order to reveal the potential structure activity relationship of novel Pt(II) complexes of antiviral nucleosides. These objectives will be attained by employing modern synthetic methods and the appropriate equipment ( outomatic synthesizer) which is in our hands. Structure - activity correlations can be reached by supporting structural stadies of synthesized and model oligonuculetotides, their adducts, and by studyng specific interactions with metal ions interchelating drugs and cross-linking Pt(II) agents. X-ray and mass spectrometry studies are imperative to support the issuse of all consecutive steps of the project. Biological support is given by NIH (NCI) Liason programme and by the supportive Central facility at Rega Institute in Leuven.