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Published online 20 May 2004

Nucleic Acids Research, 2004, Vol. 32, No. 9 2901-2911
© 2004 Oxford University Press

Clamping down on weak terminal base pairs: oligonucleotides with molecular caps as fidelity-enhancing elements at the 5'- and 3'-terminal residues

Sukunath Narayanan, Julia Gall and Clemens Richert*

Institute for Organic Chemistry, University of Karlsruhe (TH), D-76131 Karlsruhe, Germany

*To whom correspondence should be addressed. Tel: +49 721 608 2091; Fax: +49 721 608 4825; Email: cr{at}rrg.uka.de

Received March 23, 2004; Revised and Accepted April 19, 2004

The base-pairing fidelity of oligonucleotides depends on the identity of the nucleobases involved and the position of matched or mismatched base pairs in the duplex. Nucleobases forming weak base pairs, as well as a terminal position favor mispairing. We have searched for 5'-appended acylamido caps that enhance the stability and base-pairing fidelity of oligonucleotides with a 5'-terminal 2'-deoxyadenosine residue using combinatorial synthesis and MALDI-monitored nuclease selections. This provided the residue of 4-(pyren-1-yl)butyric acid as a lead. Lead optimization gave (S)-N-(pyren-1-ylmethyl)pyrrolidine-3-phosphate as a cap that increases duplex stability and base-pairing fidelity. For the duplex of 5'-AGGTTGAC-3' with its fully complementary target, this cap gives an increase in the UV melting point Tm of +10.9°C. The Tm is 6.3–8.3°C lower when a mismatched nucleobase faces the 5'-terminal dA residue. The optimized cap can be introduced via automated DNA synthesis. It was combined with an anthraquinone carboxylic acid residue as a cap for the 3'-terminal residue. A doubly capped dodecamer thus prepared gives a melting point decrease for double-terminal mismatches that is 5.7–5.9°C greater than that for the unmodified control duplex.


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