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Cyclic peptides constitute an attractive class of compounds for drug development, however the numerous problems associated with their synthesis have limited their applicability. The cyclisation step itself is particularly problematic, with solution phase cyclisations being required to be conducted under very high dilution to promote cyclisation over unwanted side reactions such as oligomerisation. In addition, epimerisation, leading to the loss of chiral integrity at the terminal residues is a major concern. Attention is now turning to biochemical cyclisation strategies, such as SICLOPPS and sortase mediated ligation, although these also come with their own inherent disadvantages, for example, in the case of sortase mediated ligation, there is significant “scarring” of the target due to the presence of a four amino acid long recognition sequence. Cyclisation using ribosomally synthesised post translationally modified enzymes is also gaining popularity. One such family of enzymes is the patellamides. PatGmac is capable of performing cyclisations on linear peptide substrates with minimal scarring compared to the aforementioned alternatives and, importantly, with no epimerisation and could constitute a greener and more facile route to cyclic peptides. The work herein details some of the investigations designed to define the range of synthetic utility and test the flexibility of the enzymes. This was done qualitatively, by designing a variety of linear peptide analogues of the natural product, homophymine A, featuring unique structural moieties and evaluating their compatibility with the enzyme. It was also done quantitatively, using an LCMS based semi-quantitative strategy, to assess differences between similar, but different, enzymes and to assess whether there were differences in how different substrates are processed by the same enzyme. In addition to this, a variety of these substrates were also assessed for their proclivity to cyclise under standard chemical conditions for comparison. Lastly, with the increasing appearance cyclic peptides and non-peptidic macrocycles in the libraries of compounds being considered for clinical trials, there is now a growing need for computational modelling of these structures. Herein, a 3D v structure for the natural product callipetin N is proposed for the first time, determined using a combination of computational and NMR techniques.