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Nucleic Acids Research, 2003, Vol. 31, No. 17 4989-4994
© 2003 Oxford University Press

Thermodynamic criteria for high hit rate antisense oligonucleotide design

O. V. Matveeva*, D. H. Mathews1, A. D. Tsodikov2, S. A. Shabalina3, R. F. Gesteland, J. F. Atkins and S. M. Freier4

Department of Human Genetics, University of Utah, 15N 2030E Room 7410, Salt Lake City, UT 84112-5330, USA, 1 Center for Human Genetics, 601 Elmwood Avenue, Box 703, Rochester, NY 14642, USA, 2 Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA, 3 NCBI, NLM, NIH, Bethesda, MD 20894, USA and 4 Isis Pharmaceuticals, Carlsbad, CA 92008, USA

*To whom correspondence should be addressed. Tel: +1 801 5815192; Fax: +1 801 5853910; Email: olgam{at}howard.genetics.utah.edu

Antisense oligonucleotides are used for therapeutic applications and in functional genomic studies. In practice, however, many of the oligonucleotides complementary to an mRNA have little or no antisense activity. Theoretical strategies to improve the ‘hit rate’ in antisense screens will reduce the cost of discovery and may lead to identification of antisense oligonucleotides with increased potency. Statistical analysis performed on data collected from more than 1000 experiments with phosphorothioate-modified oligonucleotides revealed that the oligo-probes, which form stable duplexes with RNA ({Delta}Go37 <= –30 kcal/mol) and have small self-interaction potential, are more frequently efficient than molecules that form less stable oligonucleotide–RNA hybrids or more stable self-structures. To achieve optimal statistical preference, the values for self-interaction should be ({Delta}Go37) >= –8 kcal/mol for inter-oligonucleotide pairing and ({Delta}Go37) >= –1.1 kcal/mol for intra-molecular pairing. Selection of oligonucleotides with these thermodynamic values in the analyzed experiments would have increased the ‘hit rate’ by as much as 6-fold.


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