Fabrication of cytotoxic mirror image nanopores

Neilah Firzan Ca, Kalyanashis Jana, Sreelakshmi Radhakrishnan, Rifat Aara, Mubeena S, Radhika Nair, Harsha Bajaj, Ulrich Kleinekathöfer and Kozhinjampara R. Mahendran ()
Additional contact information
Neilah Firzan Ca: Rajiv Gandhi Centre for Biotechnology
Kalyanashis Jana: Constructor University
Sreelakshmi Radhakrishnan: CSIR - National Institute for Interdisciplinary Science and Technology (NIIST)
Rifat Aara: Centre for Human Genetics
Mubeena S: Centre for Human Genetics
Radhika Nair: Centre for Human Genetics
Harsha Bajaj: CSIR - National Institute for Interdisciplinary Science and Technology (NIIST)
Ulrich Kleinekathöfer: Constructor University
Kozhinjampara R. Mahendran: Rajiv Gandhi Centre for Biotechnology

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Synthetic nanopores composed of mirror-image peptides have been reported, but not fully functional mirror-image pores. Here, we construct a monodisperse mirror-image nanopore, DpPorA and characterise its functional properties. Importantly, we alter the charge pattern and assemble a superior mirror-image pore with enhanced conductance and selectivity under different salt conditions. This pore is used for single-molecule sensing of structurally divergent biomolecules, including peptides, PEGylated polypeptides, full-length alpha-synuclein protein and cyclic sugars. Molecular dynamics simulations confirm these DpPorA are exact mirror-images of LpPorA, further revealing their structurally stable conformation. Fluorescence imaging of giant vesicles reconstituted with mirror-image peptides reveals the formation of large flexible pores facilitating size-dependent molecular transport. To explore biomedical applications, the differential cytotoxic effect of mirror-image peptides and their fluorescently tagged forms on cancer cells demonstrates a significant effect on membrane disruption and cell viability, as opposed to no effect on normal cells. We emphasize that this class of mirror-image pores can advance the development of molecular sensors and therapeutics.

Date: 2025
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DOI: 10.1038/s41467-025-64025-6

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