Modified (2′,5′)Oligonucleotides: The Influence of Structural and Steriochemical Factors on Biological and Immunotropic Activity

Abstract

The synthesis of a large number of analogs of natural 2-5A and the results of studies to clarify the relationship between the structure and spatial organization (stereochemistry) and the biological properties of analogs 2-5A have convincingly demonstrated that by changing the structure and/or stereochemistry of molecules, it is possible to achieve either strengthening of known properties or giving new ones. The replacement of the adenosine fragment with 1-deazaadenosine (c1A) or 3-deazaadenosine (c3A) at various positions of the 2-5A chain demonstrated the role of each of the nitrogen atoms of the adenine heterocycle in the processes of binding and activation of RNase L. The use of conformationally rigid fluorodeoxyadenylates in enzymatic reactions made it possible to differentiate the role of structural and stereochemical factors and demonstrate the influence of molecules’ stereochemistry on their biological properties. Oligomers with ribo-[(2′,5′)A2ARA] and lixo-[(2′,5′)A2ALA] conformation in the (A3) terminal fragment showed activity against diseases associated with disorders of T-cell immunity, autoimmune diseases, viral infections, lymphocytic malignant transformations, prevention of transplant rejection after bone marrow transplantation and, possibly, in the treatment of complications associated with the reaction of the transplanted tissue and the recipient’s tissue.