MODIFIED NUCLEOSIDES WITH RESTRICTED CONFORMATION FLEXIBILITY. STRUCTURE AND ACTIVITY

G. Gurskaya

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Str., 117984 Moscow, Russia. E-mail: gurskaya@genome.eimb.rssi.ru

Keywords: nucleoside, nucleotide analogs; x-ray structure; structure -activity correlation.

The recently found ability of some modified nucleoside 5'- triphosphates to incorporate into the growing DNA (RNA) strand and interrupt its elongation during DNA (RNA)-polymerases or viral reverse transcriptases catalysis has been widely used both for investigation of polymerases functions and development of new potential antiviral drugs.

The affinity of modified nucleoside triphosphates to each type of DNA (RNA) polymerases depends on chemical nature of substituent groups in nucleoside moiety as well as molecular conformation of nucleoside analogs.

The goal of our investigation was to study the effect of conformational factors on the activity and specificity of modified nucleosides. To achieve this, we have determined X-ray structures and analyzed their correlation with biological activity for several series of conformationally restricted compounds with expected suitability of their conformation to that of the substrate nucleoside fragment in DNA (RNA) synthesizing complexes. A definite influence of incorporation of 2'-C- and 3'-C-methyl substituents on conformation and activity of ribo- and deoxyribo-pyrimidine nucleosides was established.

The relationship between the structure and biological activity concerning different type DNA polymerases and reverse transcriptases was studied for conformationally rigid compounds: 2',3'-dideoxy-2',3'-didehydronucleosides, the nucleosides containing in their furanose cycles an additional three-membered fused ring in endo- or exoorientation, and for the latters with the second substituent - oxymethyl group at the 4'-C- position.

The examined compounds were synthesized mainly in the Institute of Molecular Biology RAN, Moscow (lab. of Prof. A. Krayev- sky) and in Sechenov Medical Academy, Moscow ( Dr. I. Fedorov).

The work was supported by the State Program National Prio- rities in Medicine and Public Health: AIDS ( grants No. SP 054 and SP -04) and Russian Foundation for Basic Research ( grants No. 93-04-07957).