Synthesis and Improved Cross-Linking Properties of C5-Modified Furan Bearing PNAs

• Main Authors: Joke Elskens, Alex Manicardi, Valentina Costi, Annemieke Madder, Roberto Corradini
• Format: Article
• Language: English
• Published: MDPI AG 2017-11-01
• Series: Molecules
• Subjects: PNA; backbone modification; furan; crosslinking; chiral monomers
• Online Access: https://www.mdpi.com/1420-3049/22/11/2010

Over the past decades, peptide nucleic acid/DNA (PNA:DNA) duplex stability has been improved via backbone modification, often achieved via introducing an amino acid side chain at the α- or γ-position in the PNA sequence. It was previously shown that interstrand cross-linking can further enhance the binding event. In this work, we combined both strategies to fine-tune PNA crosslinking towards single stranded DNA sequences using a furan oxidation-based crosslinking method; for this purpose, γ-l-lysine and γ-l-arginine furan-PNA monomers were synthesized and incorporated in PNA sequences via solid phase synthesis. It was shown that the l-lysine γ-modification had a beneficial effect on crosslink efficiency due to pre-organization of the PNA helix and a favorable electrostatic interaction between the positively-charged lysine and the negatively-charged DNA backbone. Moreover, the crosslink yield could be optimized by carefully choosing the type of furan PNA monomer. This work is the first to describe a selective and biocompatible furan crosslinking strategy for crosslinking of γ-modified PNA sequences towards single-stranded DNA.