BLOCK POLYCATIONIC OLIGONUCLEOTIDE DERIVATIVE - SYNTHESIS AND INHIBITION OF HERPES-VIRUS REPRODUCTION

The block polycationic oligonucleotide (oligo) consisting of a phospho diester 12-mer linked to the polycation chain at the 3'-end and choles teryl group at the 5'-end was synthesized. The polycation chain was gr own on the solid support using the monomer, H-phosphonate of 1-O-(4,4' -dimethoxytrityl)1,3-butanediol. Amino groups were introduced in the p olymer backbone using 1,4-diaminobutane, and then the oligo chain was formed at the free end of the polymer. The last stage of the synthesis was the attachment of the cholesteryl group to the 5'-end of the olig o prior to cleavage and deprotection of the copolymer. The nucleotide sequence of this copolymer, CGTTCCTCCTGC, was complementary to the spl icing site of immediate early (IE) mRNA 4 and 5 of herpes simplex viru s type 1 (HSV-1). The stability of the duplexes formed between the cop olymer and the complementary 12-mer was similar to that of unmodified oligo. The stability of the block polycationic oligo against phosphodi esterase digestion was significantly increased compared to that of the unmodified oligo. The block polycationic oligo inhibited the reproduc tion of HSV-1 in Vero cells; however, the effect was significantly les s than the effect of 12-mer oligo modified with cholesterol at the 5'- end. The decreased antiviral activity of the copolymer is explained by the polycation-induced stimulation of the virus infection.