1 publication

1 publication

Modular Design of G-Quadruplex MetalloDNAzymes for Catalytic C–C Bond Formations with Switchable Enantioselectivity

Clever, G.H.

J. Am. Chem. Soc. 2021, 143, 3555-3561, 10.1021/jacs.0c13251

Metal-binding DNA structures with catalytic function are receiving increasing interest. Although a number of metalloDNAzymes have been reported to be highly efficient, the exact coordination/position of their catalytic metal center is often unknown. Here, we present a new approach to rationally develop metalloDNAzymes for Lewis acid-catalyzed reactions such as enantioselective Michael additions. Our strategy relies on the predictable folding patterns of unimolecular DNA G-quadruplexes, combined with the concept of metal-mediated base-pairing. Transition-metal coordination environments were created in G-quadruplex loop regions, accessible by substrates. Therefore, protein-inspired imidazole ligandoside L was covalently incorporated into a series of G-rich DNA strands by solid-phase synthesis. Iterative rounds of DNA sequence design and catalytic assays allowed us to select tailored metalloDNAzymes giving high conversions and excellent enantioselectivities (≥99%). Based on their primary sequence, folding pattern, and metal coordination mode, valuable information on structure–activity relationships could be extracted. Variation of the number and position of ligand L within the sequence allowed us to control the formation of (S) and (R) enantiomeric reaction products, respectively.

Metal: Cu
Ligand type: DNA (G quadruplex)
Host protein: metalloDNAzyme
Anchoring strategy: Imidazole ligandoside
Optimization: Genetic
Reaction: Michael addition
Max TON: ---
ee: >99
PDB: ---
Notes: Km 35.2 uM, vmax-8.2 nM min-1