3 '-deoxy-3 '-fluoro analogues of 2-5A core trimers: Their effect on the lytic activity of human NK lymphocytes

The effect of core trimers, (2'-5')-analogues of oligoadenylic acid contain ing 9-(3-deoxy-3-fluoro-beta-D-xylofuranosyl)adenine (A(F)) and 3'-deoxy-3' -fluoroadenosine (A(F)) in various positions of the oligomer chain, on the lyric activity of human natural killer tells (NK cells) was studied in thre e different ways. The cellular cytotoxicity was determined using a highly s ensitive nonradioactive approach employing a chelate europium-diethylenetri amino-pentaacetic acid complex (Eu-DTPA). It was shown that all fluorodeoxy analogues enhance the lyric activity of intact NK lymphocytes, which follow s from the lysis rare constant k(2). At the same time, the substitution of either the central adenosine fragment or (to a greater extent) the 5'-termi nal residue of (2'-5')A(3) with A(F) causes a decrease in the number of act ive NK cells, which, unlike the case of the natural core trimer, leads to a loss of the capacity to increase the activity of NK. By contrast, isomeric ribo-analogues, (2'-5')(A(F))A(2) and(2'-5')A(A(F))A, and trimers with the 2'(3')-terminal nucleotide substituted by A(F) or A(F) increased the activ ity of NK cells with an effectiveness close to or higher than the natural t rimer (2'-5')A(3). Inasmuch as isomeric xylo- and ribo-3'-deoxy-3'-fluoroan alogues of (2'-5')A(3) are stereochemically modified oligomers, the data un ambiguously suggest that the spatial structure of these trimers affects the increase in the lytic activity of NK cells.