Efforts toward Expansion of the Genetic Alphabet: Optimization of Interbase Hydrophobic Interactions

J. Am. Chem. Soc., 122 (32), 7621 -7632, 2000. 10.1021/ja0009931 S0002-7863(00)00993-8
Web Release Date: July 28, 2000

Efforts toward Expansion of the Genetic Alphabet: Optimization of Interbase Hydrophobic Interactions

Yiqin Wu, Anthony K. Ogawa, Markus Berger, Dustin L. McMinn, Peter G. Schultz,* and Floyd E. Romesberg*

Contribution from the Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037

Received March 20, 2000

Abstract:

Six novel unnatural nucleobases have been characterized that form stable base pairs in duplex DNA, relying not on hydrogen bonds, but rather on interbase hydrophobic interactions. These nucleobases are derivatives of the hydrophobic base pair between 7-azaindole (7AI) and isocarbostyril (ICS). Derivatives of 7AI and ICS were examined that have increased hydrophobic surface area, as well as increased polarizability. As observed with 7AI and ICS, these derivatives are recognized as substrates by Klenow fragment of Escherichia coli DNA polymerase I. The unnatural base pair between pyrrolopyrizine (PP) and C3-methylisocarbostyril (MICS) is enzymatically incorporated into DNA with high efficiency (k_cat/K_M = 10⁶ M^-¹ min^-¹) and moderate selectivity. These studies represent a significant step toward the generation of a stable, orthogonal base pair that can be enzymatically incorporated into DNA with good fidelity.

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