Interaction of HIV-1 reverse transcriptase with new minor groove binders and their conjugates with oligonucleotides

Abstract

The effect on polymerization catalyzed by reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1) was studied for new nonnatural regular minor groove binders (MGBs) containing two to four imidazole, pyrrole, or thiazole residues and for MGB conjugates with oligonucleotides. Poly(A)- oligo(U), poly(A)-oligo(dT), poly(dA)-oligo(U), poly(dA)-oligo(dT), and activated DNA were used as model template-primer complexes. The half-inhibitory concentrations (I 50) of the oligopeptides were shown to strongly depend on the structure of the template-primer complex and on the number and type of heterocyclic rings in the MGB. With most compounds tested, I 50 varied from 7.7 × 10-3 to 1.0 × 10 -5 M. Minimal affinity of MGBs was observed with the poly(A)-oligo(U) complex. However, some imidazole- and pyrrole-containing MGBs showed unusually high affinity for the complex of RT with the template-primer duplex, I 50 ranging from 3 × 10-9 to 4 × 10 -8 M. In most cases, conjugates of thiazole-containing MGBs with oligonucleotides completely or partly complementary to the template had an affinity one to four orders of magnitude higher than free thiazole carboxamides. Possible causes of the dependence of I 50 on the structure of template-primer complexes, MGBs, and their conjugates with oligonucleotides are considered. © 2005 Pleiades Publishing, Inc.