The development of novel biocatalytic supramolecular structures mimicking the active center of natural ribonucleases and capable of cleaving RNA targets can provide a basis for generating new useful biological tools and powerful therapeutics, affecting specific messenger RNAs and viral genomic RNAs. Recently, a new type of chemical nuclease (1-4), showing very unusual catalytic and structural properties, was discovered. These novel oligonucleotide-mediated chemical nucleases were constructed by chemical conjugation of short, catalytically inactive oligopeptides containing alternating basic and hydrophobic amino acids with an oligonucleotide component (1-4). The most remarkable feature of these novel biocatalysts was that the conjugation of peptide and oligonucleotide seems to produce a new, hybrid type of molecule that can synergistically combine the individual properties of the two components to yield a new and unusual catalytic ability.

In this research we present structural aspects of a new type of catalytic artificial ribonucleases with high catalytic turnover and efficiency, using 2D NMR spectroscopy and molecular modelling. Our structural studies of these oligonucleotide-mediated chemical nucleases revealed a clear Structure-Function correlation in terms of their ability to cleave single-stranded regions of an RNA target. Spectroscopic and computational data obtained so far provides sufficient evidence that both oligonucleotide and peptide cross-modulate each other?s conformations leading to a formation of a new entity with unique structural and functional properties. The oligonucleotide component seems to induce an `active' conformation of the peptide and hence significantly enhance its catalytic performance. The manipulation of the structural properties of these catalytic nucleases may lead to a creation of new types of synthetic ribonucleases of high activity and desired base-specificity.

References and Footnotes

1. Pyshnyi, D., Repkova, M., Lokhov, S., Ivanova, E., Venyaminova, A., Zarytova, V. Nucleosides & Nucleotides, 16, 1571?1574 (1997).
2. Mironova, N. L., Pyshnyi, D. V., Ivanova, E. M., Zenkova, M. A., Gross, H. J., and Vlassov, V. V. Nucl Acids Res 32, 1928-1936 (2004).
3. Mironova, N. L., Pyshnyi, D. V., Stadler, D. V., Prokudin, I. V. Boutorine, Y. I., Ivanova, E. M., Zenkova, M. A., Gross, H. J., and Vlassov, V. V. J Biomol Struct Dyn 23, 591 602 (2006).
4. Mironova, N. L., Pyshnyi, D. V., Shtadler, D. V., Fedorova, A. A., Vlassov, V. V., Zenkova, M. A. Nucl Acids Res 35, 2356-2367 (2007).