Peptides are effective pharmaceutical agents. However, their full therapeutic potential is limited by their lack of oral bioavailability. Orally active drugs need to simultaneously be metabolically stable, membrane permeable and active against receptor targets. This trifecta is difficult to achieve for peptides due to their inherent chemical properties. A well-known example of a peptide that is orally active without formulation enhancements is cyclosporin A (CSA) and is often cited as proof of concept that oral peptide therapeutics are a possibility.¹ Although developing peptides that are active and metabolically stable is challenging, membrane permeation remains the limiting factor in developing oral peptides drugs. Previous works on peptide permeability have established several features that enhance membrane permeation such as cyclisation, reduction of hydrogen-bond count or N-methylation.² However, these studies have been applied to non-bioactive peptide derivatives. Hence, the challenge remains in designing more drug-like peptides by incorporating chemical characteristics that favour membrane permeability whilst maintaining acceptable metabolic stability and activity against a druggable target. Somatostatin receptors are well-studied drug targets that are modulated by cyclic peptides. This family of GPCRs consists of five subtypes that are responsible for a diverse range of physiological functions such as hormone secretion regulation.³ Peptide therapeutics that target somatostatin exist as injectables. Patient compliance and accessibility could be greatly improved by developing an orally bioavailable peptide analogue for somatostatin treatments. In this work, we aimed to improve the membrane permeability of previously reported, bioactive somatostatin analogues by applying established rationales. The membrane permeability of peptide analogues was tuned by increasing hydrophobicity, reducing hydrogen bonds, or varying sidechain chirality. Cellular permeability of our analogues was modelled using the parallel artificial membrane permeability assay (PAMPA). Binding of peptides was also measured through a binding assay. Computational models have been used to rationalise the permeability of the designed peptides.