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De novo designed peptides for cellular delivery and subcellular localisation

Rhys, Guto G., Cross, Jessica A., Dawson, William M., Thompson, Harry F., Shanmugaratnam, Sooruban, Savery, Nigel J., Dodding, Mark P., Höcker, Birte and Woolfson, Derek N. 2022. De novo designed peptides for cellular delivery and subcellular localisation. Nature Chemical Biology 18 (9) , pp. 999-1004. 10.1038/s41589-022-01076-6
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Increasingly, it is possible to design peptide and protein assemblies de novo from first principles or computationally. This approach provides new routes to functional synthetic polypeptides, including designs to target and bind proteins of interest. Much of this work has been developed in vitro. Therefore, a challenge is to deliver de novo polypeptides efficiently to sites of action within cells. Here we describe the design, characterisation, intracellular delivery, and subcellular localisation of a de novo synthetic peptide system. This system comprises a dual-function basic peptide, programmed both for cell penetration and target binding, and a complementary acidic peptide that can be fused to proteins of interest and introduced into cells using synthetic DNA. The designs are characterised in vitro using biophysical methods and X-ray crystallography. The utility of the system for delivery into mammalian cells and subcellular targeting is demonstrated by marking organelles and actively engaging functional protein complexes.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Publisher: Nature Research
ISSN: 1552-4450
Date of First Compliant Deposit: 1 December 2022
Date of Acceptance: 3 June 2022
Last Modified: 02 Dec 2022 05:51

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