ABSTRACT
We have prepared cyclic peptide nucleic acids (PNAs). These compounds do not bind complementary nucleic acids. One carboxylic ester group was introduced in the backbone of the cyclic PNAs. This group is cleaved in the presence of Cu(2+) or coordinatively unsaturated Cu(2+) complexes. The cleavage products are linear PNAs. In contrast to the cyclic PNAs, they are efficient nucleic acid binders. The rate of formation of the linear PNAs is proportional to the concentration of the cleaving agents. Therefore, one may apply highly sensitive methods of detection of linear PNAs for determination of Cu(2+) concentration. In particular, we have demonstrated that both fluorescent spectroscopy in combination with molecular beacons and MALDI-TOF mass spectrometry are suitable for the detection of Cu(2+). A range of related divalent metal ions and Eu(3+), Ln(3+), Pr(3+), Ce(3+), and Zr(4+) do not interfere with Cu(2+) detection.
Subject(s)
Copper/pharmacology , Peptide Nucleic Acids/chemistry , Peptides, Cyclic/chemistry , Adenosine Triphosphate/chemistry , Cations, Divalent/chemistry , Cations, Divalent/pharmacology , Chromatography, High Pressure Liquid , DNA/chemistry , Deoxyribonucleases/drug effects , Deoxyribonucleases/metabolism , Models, Molecular , Molecular Conformation , Nucleic Acid Hybridization , Peptide Nucleic Acids/drug effects , RNA/chemistry , Ribonucleases/drug effects , Ribonucleases/metabolism , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methodsABSTRACT
The efforts towards peptide nucleic acid (PNA) drug discovery using cellular RNAs as molecular targets is briefly reviewed, with special emphasis on recent developments. Special attention is given to cellular delivery in vivo bioavailability and the possibilities of using PNA oligomers to (re)direct alternative splicing of pre-messenger (m)RNA.
Subject(s)
Peptide Nucleic Acids/drug effects , RNA/drug effects , Animals , Biological Availability , Drug Delivery Systems , Humans , RNA/pharmacokinetics , RNA Viruses/drug effects , RNA, Messenger/drug effectsABSTRACT
A cyclic molecule 1 constituted by a hepta-peptide nucleic acid sequence complementary to the apical loop of domain IV of hepatitis C virus (HCV) internal ribosome entry site (IRES) RNA has been prepared via a 'mixed' liquid-phase strategy, which relies on easily available protected PNA and poly(2-aminoethylglycinamide) building blocks. This compound 1 has been elaborated to mimic 'loop-loop' interactions. For comparison, its linear analog has also been investigated. Although preliminary biological assays have revealed the ability of 1 to inhibit in vitro the HCV IRES-dependent translation in a dose-dependent manner, the linear analog has shown a slightly higher activity.
