Macrocyclic peptides have the potential to bind to biomolecular surfaces that are challenging to target with small molecules, due to the lack of well-defined binding pockets. Pocketless surfaces are commonly found in protein-protein and protein-nucleotide interactions and therefore make attractive therapeutic targets. Together, this makes the class of macrocyclic peptides interesting for therapeutic development, but they tend to suffer from low membrane permeability, limiting their use as such targets are often found intracellularly. Although low permeability is common, there are exceptions to the rule including numerous natural product cyclic peptides. Nature has developed several methods to improve on cell-permeability including backbone N-methylation and the introduction of aromatic groups in peptide backbones (Fig. ). A well-studied example of the first method is Cyclosporin A and it was found that by methylation of specific backbone amides, intramolecular hydrogen bonds (IMHBs) are induced, forcing hydrophobic amino acid side chains to the periphery. In this conformation, the polar backbone amides are shielded effectively reducing the polar surface area (PSA) of the macrocycle during the transition through the hydrophobic parts of the cellular membrane. Although the strategy is robust, it is difficult to design, and many variations of the methylation pattern have to be explored either by synthesizing them individually or in a combinatorial fashion. An alternative to N-methylation is the inclusion of aromatic groups into the backbone of a peptide which serves the same purpose: to reduce PSA and induce IMHBs. It is observed in many membrane permeable natural product cyclic peptides including Patellamide C and Dendroamide A, which both contain several oxazolines and thiazolines. Other well-studied examples include the Sanguinamides and Danamides (Fig. ), which have a single thiazoline in their backbone, and were found to be cell-permeable and certain variants that were orally available. Synthetic methods to incorporating aromatic heterocycles into cyclic peptide backbones, inspired by the previously described natural products, have been reported. These include oxadiazole grafts, developed by the Yudin group, which were shown to be effective in promoting cell permeability. In another study, the same group systematically incorporated multiple aromatic groups in a model peptide. Although permeability generally increased with an increasing number of heterocycles, this was not always the case. Recently, Ly et al. studied the effect of furan and pyrrole aromatics as part of small cyclic peptides. The report described large differences in passive permeability between compounds with small chemical changes, which the authors mainly attributed to changes in IMHBs. In both studies, the aromatic backbone modification was combined with exchange of amino acid side-chains or backbone alkylation to further improve the cell-permeability. Based on this previous work, we envisioned that the cell permeability of a biologically active peptide could be enhanced by the incorporation of an aromatic group in its backbone. To preserve the peptide's biologically active structure, it is crucial to avoid modifications to the remaining amino acids and maintain the biologically active conformation as much as possible. To explore this approach, we proposed to study simple aromatic groups and to evaluate how minor modifications to these groups influence cell-permeability.