Fig. 1. Cortistatin and Somatostatin sequence comparison, analogue design and NMR conformers.

a Sequence comparison of human Somatostatin (SST) to rat, mouse and human Cortistatins (CST). b Backbone superposition of the 10-lowest energy conformers. The peptide backbone is shown in gold and the N- and C-terminus residues, as well as the disulfide bond are labelled. Representative aromatic clusters. All side chains are shown to facilitate structural analysis. Side chains participating in the interactions are specifically labelled. c Schematic representation of Cortistatin-14 sequence. Positions Xa, Xb, Xc and Xd have been mutated to prepare the analogues. Native CST was also synthesised for the NMR and functional studies. Sequences of the analogues prepared in this work. Substitutions are coloured. Synthetic scheme is displayed as Supplementary Fig. 1a. d Schematic representations of the relative affinities of SST, CST and analogues A2-A5 for the different Somatostatin receptors (SSTR1-SSTR5) Supplementary Fig. 1b. The relative affinities are represented based on the determined IC₅₀ values. The values are collected as Supplementary Table 1.