Hybridization between “Six-Membered” Nucleic Acids: RNA as a Universal Information System Luc Kerremans, Guy Schepers, Jef Rozenski, Roger Busson, Arthur Van Aerschot, and Piet Herdewijn* ,† Katholieke UniVersiteit LeuVen, Rega Institute, Minderbroedersstraat 10, B-3000 LeuVen, Belgium piet.herdewijn@rega.kuleuVen.ac.be Received May 28, 2001 (Revised Manuscript Received October 3, 2001) ABSTRACT Within the polyA:polyT recognition system, cross-pairing between several nucleic acids with a phosphorylated six-membered carbohydrate (mimic) as repeating unit in the backbone structure has been observed. All investigated nucleic acids (except for -homo-DNA) hybridize with RNA, leaving RNA as a versatile biopolymer for informational transfer. On one hand, it is now commonly accepted that the RNA- world preceded the DNA-world. On the other hand, it is hard to believe that a -D-ribonucleotide, because of its structural and stereochemical complexity, was the first nucleotide formed by self-assembly of organic matter. The -D- ribonucleotides are, most likely, themselves the end result of a stepwise constitutional metamorphosis process of nucleotide building blocks, finally leading to the selection of RNA as a biopolymer, which is able to generate life with a potential to evolve. 1,2 This molecular metamorphosis process has followed the rules of molecular assembly and reorganization, while retaining informational capacity. 1,2 This hypothetical view on life presumes that informational transfer between biopolymers to and from RNA (i.e. to DNA) is easily occurring. In this study we investigated RNA’s potential for hybrid- ization with a series of distant related nucleic acids structures, containing a six-membered phosphorylated carbohydrate (mimic) backbone. The hybridization is studied within the simplest recognition mode (oligoadenylate-oligothymidy- late). The modified nucleic acids that have been investigated on their base pairing properties have mostly a five-membered phosphorylated carbohydrate (mimic) as repeating unit of the backbone structure. These oligonucleotides are usually screened for cross-pairing with RNA (for antisense purposes or for information exchange with natural nucleic acids) and for self-hybridization (organization in higher molecular structures via base pairing). The conformational prerequisites of oligonucleotides with a five-membered carbohydrate (mimic) in the backbone structure for hybridization with RNA have been analyzed. 3-4 Extensive information about the selectivity of hybridization of oligonucleotides with a six-membered carbohydrate (mimic) is lacking. It has been observed that potentially natural nucleic acid alternatives of the (6′f 4′) hexopyra- nosyl (including the -homo-DNA model) and the (4′ f 2′) pentopyranosyl families, where base pairing is orthogonal to that of the natural nucleic acids, do not cross pair with RNA and DNA. 1 In all these cases, the nucleobases are equatorially positioned on the pyranosyl chains. In cases were † Tel. +32-16-337387. Fax +32-126-337340. (1) Schoning, K.; Scholz, P.; Guntha, S.; Wu, X.; Krishnamurthy, R.; Eschenmoser, A. Science 2000, 290, 1347-1351. (2) Joyce, G. F.; Orgel, L. E. In The RNA World; Gesteland, R. F., Cech, T. R., Atkins, J. F., Eds.; Cold Spring Harbor Laboratory Press: 1999; pp 49-77. (3) Herdewijn, P. Liebigs Ann. 1996, 1337-1348. (4) Herdewijn, P. Biochem. Biophys. Acta 1999, 19, 167-179. ORGANIC LETTERS 2001 Vol. 3, No. 26 4129-4132 10.1021/ol016183r CCC: $20.00 © 2001 American Chemical Society Published on Web 11/28/2001