A bridge between the RNA and protein worlds? Accelerating delivery of chemical reactivity to RNA and DNA by a specific short peptide (AAKK)(4)

Background: RNA can catalyze diverse chemical reactions, leading to the hyp othesis that an RNA world existed early in evolution. Today, however, catal ysis by naturally occurring RNAs is rare and most chemical transformations within cells require proteins. This has led to interest in the design of sm all peptides capable of catalyzing chemical transformations. Results: We demonstrate that a short lysine-rich peptide (AAKK)(4) can deli ver a nucleophile to DNA or RNA and amplify the rate of chemical modificati on by up to 3400-fold. We also tested similar peptides that contain ornithi ne or arginine in place of lysine, peptides with altered stereochemistry or orientation, and peptides containing eight lysines but with different spac ing. Surprisingly, these similar peptides function much less well, suggesti ng that specific combinations of amino acids, charge distribution, and ster eochemistry are necessary for the rate enhancement by (AAKK)(4). Conclusions: By appending other reactive groups to (AAKK)(4) it should be p ossible to greatly expand the potential for small peptides to directly cata lyze modification of DNA or RNA or to act as cofactors to promote ribozyme catalysis. (C) 2001 Published by Elsevier Science Ltd.