Peptide nanotubes formed through secondary and tertiary structures are an emerging area of chemical biology. Head-to-tail cyclised peptides with alternating d/l-amino acids form nanotubes through a well-ordered hydrogen bonding network.¹ Cyclic peptide nanotubes (CPNs) based on these materials are able to form long networks of nanotubes that demonstrate applications in a number of areas such as drug delivery systems, biomimetic membrane channels and bioorganic electronic devices.² CPNs generated from self-assembled monomers have limited control over the assembly mechanism and consequently the supramolecular structure. This can be overcome by covalently tethering monomeric cyclic peptides to improve control over the self-assembly.³ Symmetrical tethers have shown to be an effective tethering strategy, however, it limits the ability to selectively functionalise CPNs.³

By introducing asymmetrical tethering strategies, we can develop more specific structures tailored for more specific applications. This work looks to design and synthesise asymmetric CPNs that are able to embed within membranes. Several covalently tethered asymmetric tetramer designs were computationally modelled to evaluate their stability in a membrane environment. The desirable tetramer designs were attempted to be synthesised using a variety of orthogonal protecting groups and tethering strategies.