A New Concept for the Design of Antisense Oligonucleotides Based on Nucleic Acid Thermostability

Authors: Naoki Sugimoto; Isao Yasumatsu

Source: Current Medicinal Chemistry - Anti-Cancer Agents, Volume 1, Number 1, May 2001 , pp. 95-112(18)

Publisher: Bentham Science Publishers

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Abstract:

The antisense method is one of the most promising anti-cancer methods, however, the design of antisense oligonucleotides is difficult because many factors affecting their activitiy and stability must be considered. Recently, the oligonucleotide stabilities related to the antisense effects were quantitatively investigated based on nearest-neighbor parameters. We demonstrated that DG37, hyb , a free energy change for the hybridization of antisense oligodeoxynucleotides (ODNs) with target RNAs is related to the RNase H cleavage of TAg (SV40 large T antigen) mRNA, the expression of a rabbit globin mRNA, and the protein function encoded by hMDR1 (human multidrug resistance-1) mRNA, while DG37, hp , a free-energy change for hairpin formations of the antisense ODNs significantly affected the arrest efficiency of the DHFR (dihydrofolate reductase) mRNA transcription, the expression of the pro alpha1(I) chain of human, and the hybridization extent for HIV-1 alpha-1. For ras RNA (Ha-ras mRNA), DG37, sc , a free energy change for the conformational change of the mRNA required for antisense ODN binding showed the best correlation with the equilibrium constants for the hybridization with their target RNA. On the other hand, the antisense effects ifor the HSV-1 IE5 (herpes simplex virus type 1 immediate early pre-mRNA5) showed less of a relationship to the hybridization stability of the antisense ODNs with the target pre-mRNA, because the antisense ODNs targeting the pre-mRNA must collapse its secondary structure around the splicing site to cancel out the expected antisense effects. Based on these results, we illustrate a new concept for the design of antisense ODNs based on deltaG 37, hyb , deltaG 37, hp , and deltaG 37, sc .

Keywords: Antisense Oligonucleotides; Nucleic Acid Thermostability; antisense oligodeoxynucleotides; phosphorothioate; phosphodiester dodecanucleotides

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1568011013354813

Affiliations: 1: Department of Chemistry,Faculty of Science, Konan University, 8-9-1 Okamoto, Higashinada-ku, Kobe 658-8501, Japan.

Publication date: 2001-05-01

A New Concept for the Design of Antisense Oligonucleotides Based on Nucleic Acid Thermostability

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