Peptide nucleic acids (PNAs) are designer nucleic acid analogues which replace the native sugar phosphate backbone with a peptidic scaffold to display the nucleobases.[1] This substitution removes the associated negative charge and thereby enables a PNA strand to hybridise both to DNA and to itself with increased affinity (allowing for comparable affinity to be achieved with significantly shorter sequences).[2] As such, PNA has been widely applied in place of native nucleic acids in a range of applications such as nucleic acid sensing, the formation of supramolecular architectures, gene editing and antisense therapies. PNAs also enjoy improved metabolic stability and ease of synthesis compared to their native counterparts and can therefore be modified to tune their biological properties. In particular, PNA monomers with chirality introduced at the γ position can be used to modulate the inherent helicity of the PNA to prevent interactions with native nucleic acids, thereby preventing off target interactions and increasing specificity. Such modification at the γ-position also facilitates tuning of the physicochemical properties of PNA, particularly in terms of solubility and aggregation propensity. However, accessing γ-modified PNA monomers requires lengthy synthesis and incorporation of such monomers often leads to inefficient on-resin synthesis. We have developed a universal γ-propargyl PNA backbone from either D or L serine which facilitates late-stage functionalisation via on-resin copper(I)- catalysed azide-alkyne cycloaddition (CuAAC) and demonstrated the utility of these monomers in PNA-based hybridisation chain reactions (HCRs).[3] We have also extended the application of HCRs using DNA-based systems to demonstrate selective cancer cell killing in mixed cell populations.[4]
References
[1] P. E. Nielsen, M. Egholm, R. H. Berg, O. Buchardt, Science 1991, 254, 1497-1500.
[2] M. Egholm, O. Buchardt, L. Christensen, C. Behrens, S. M. Freier, D. A. Driver, R. H. Berg, S. K. Kim, B. Norden, P. E. Nielsen, Nature 1993, 365, 566-568.
[3] M. López-Tena, E. E. Watson, P. Romanens, N. Winssinger, Helvetica Chimica Acta 2023, 106, e202300110
[4] S.-K. Chen, M. López-Tena, F. Russo, E. E. Watson, M. Dockerill, J. C. Garcia, S. Barluenga, N. Winssinger, Nat. Nanotechnol. 2026, doi:10.1038/s41587-026-03044-0