Cyclic peptides composed of alternating D and L amino acids (CPs) are well-known to assemble spontaneously through  b-sheet-like H-bonding to form extended nanostructures.^1,2 These modular materials have great potential as versatile nanomaterials. However, the useful development of CP nanomaterials requires practical methods to control their assembly. In this work, we have developed novel, heterogeneous, covalently linked CP tetramers that achieve local control over the CP subunit order and composition through coupling of amino acid side-chains using copper-activated azide–alkyne cycloaddition and disulfide bond formation.³ Cryo-transmission electron microscopy revealed the formation of highly ordered, fibrous nanostructures, while NMR studies showed that these systems have strong intramolecular H-bonding in solution. The introduction of inter-CP tethers is expected to enable the development of complex nanomaterials with controllable chemical properties, facilitating the development of precisely functionalized or “decorated” peptide nanostructures.

1. Ghadiri, M. R.; Granja, J. R.; Milligan, R. A.; McRee, D. E.; Khazanovich, N. Self-assembling organic nanotubes based on a cyclic peptide architecture. Nature 1993, 366, 324-7.
2. Silk, M. R.; Newman, J.; Ratcliffe, J. C.; White, J. F.; Caradoc-Davies, T.; Price, J. R.; Perrier, S.; Thompson, P. E.; Chalmers, D. K. Parallel and antiparallel cyclic d/l peptide nanotubes. Chem Commun 2017, 53, 6613-6616.
3. Silk, M. R.; Mohanty, B.; Sampson, J. B.; Scanlon, M. J.; Thompson, P. E.; Chalmers, D. K. Controlled Construction of Cyclic d / l Peptide Nanorods. Angew Chem Int Ed Engl 2019, 58, 596-601.