[3'-Deoxy-3'-fluoro analogs of core trimers of 2-5A: effect on lytic activity of human NK-lymphocytes].
The effect of core trimers, (2'-5')-analogues of oligoadenylic acid containing 9-(3-deoxy-3-fluoro-beta-D-xylofuranosyl)adenine (AF) and 3'-deoxy-3'-fluoroadenosine (AF) in various positions of the oligomer chain, on the lytic activity of human natural killer cells (NK cells) was studied in three different ways. The cellular cytotoxicity was determined using a highly sensitive nonradioactive approach employing a chelate europium-diethylenetriamino-pentaacetic acid complex (Eu-DTPA). It was shown that all fluorodeoxyanalogues enhance the lytic activity of intact NK lymphocytes, which follows from the lysis rate constant k2. At the same time, the substitution of either the central adenosine fragment or (to a greater extent) the 5'-terminal residue of (2'-5')A3 with AF causes a decrease in the number of active 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')(AF)A2 and (2'-5')A(AF)A, and trimers with the 2'(3')-terminal nucleotide substituted by AF or AF increased the activity of NK cells with an effectiveness close to or higher than the natural trimer (2'-5')A3. Inasmuch as isomeric xylo- and ribo-3'-deoxy-3'-fluoroanalogues of (2'-5')A3 are stereochemically modified oligomers, the data unambiguously suggest that the spatial structure of these trimers affects the increase in the lytic activity of NK cells.
Kalinichenko
E N
EN
Institute of Bioorganic Chemistry, Belorussian Academy of Sciences, Minsk, Belarus.
Podkopaeva
T L
TL
Kelve
M
M
Saarma
M
M
Mikhaĭlopulo
I A
IA
D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D003839:Deoxyadenosines / Q000494:pharmacology*; D006801:Humans; D007694:Killer Cells, Natural / Q000737:chemistry / Q000276:immunology*
D003839:Deoxyadenosines; C062976:3'-fluoro-3'-deoxyadenosine
3'-Dezoksi-3'-ftoranalogi korovykh trimerov 2-5A: vliianie na liticheskuiu aktivnost' NK-limfotsitov cheloveka.