title: Recognition of DNA/RNA bulges by antimicrobial and antitumor metallohelices.
abstract: Bulged structures have been identified in nucleic acids and have been shown to be linked to biomolecular processes involved in numerous diseases. Thus, chemical agents with affinity for bulged nucleic acids are of general biological significance. Herein, the mechanism of specific recognition and stabilization of bulged DNA and RNA by helical bimetallic species was established through detailed molecular biophysics and biochemistry assays. These agents, known as 'flexicates', are potential mimetics of α-helical peptides in cancer treatment, exhibiting antimicrobial and antitumor effects. The flexicates have positive impacts on the thermal stability of DNA duplexes containing bulges, which means that the flexicates interact with the duplexes containing bulges, and that these interactions stabilize the secondary structures of these duplexes. Notably, the stabilising effect of the flexicates increases with the size of the bulge, the maximal stabilization is observed for the duplexes containing a bulge composed of at least three bases. The flexicates bind most preferentially to the bulges composed of pyrimidines flanked on both sides also by pyrimidines. It is suggested that it is so because these bulges exhibit greatest conformational variability in comparison with other combinations of bases in the bulge loop and bases flanking the bulge. Finally, the results indicate that there is only one dominant binding site for the flexicates on the DNA and RNA bulges and that the flexicates bind directly to the bulge or in its close proximity. It is also shown that the flexicates effectively bind to RNA duplexes containing the bulged region of HIV-1 TAR RNA.
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265 Brno, Czech Republic. brabec@ibp.cz.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Malina
authors.forename: Peter
authors.initials: P
authors.lastname: Scott
authors.forename: Viktor
authors.initials: V
authors.lastname: Brabec
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009690:Nucleic Acid Conformation / Q000187:drug effects*; D009691:Nucleic Acid Denaturation / Q000187:drug effects; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology; D012313:RNA / Q000737:chemistry* / Q000378:metabolism; D020871:RNA Stability / Q000187:drug effects; D012328:RNA Viruses / Q000737:chemistry / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D012313:RNA; D004247:DNA