Proteins are incredible yet complex biomolecules with unique shapes. The primary protein structure is a polypeptide made of amino acids, the simplest protein building blocks, which form long chains when linked together. However, the resulting linear structures must be folded into specific shapes. Proteins are reshaped in native environments, where spontaneous protein folding and unfolding can occur. This dynamic process is influenced by covalent peptide and disulphide bonds that interconnect distant cysteine residues, as well as weaker non-covalent interactions. Initiating from a simple polypeptide chain, protein folding is facilitated by various non-covalent forces. These forces influence stability and flexibility, ultimately defining the protein function. Various cross-linking tools can facilitate correct folding in synthetic peptides, including covalent stapling and non-covalent stabilisation methods. In synthetic polypeptides, non-covalent structural stabilisation involves ionic bridging, aromatic π-stacking and metal coordination, where weak interactions can improve fold integrity without imposing significant structural limitations. Both in silico techniques and strategic chemical synthesis have influenced medicinal chemistry, transforming unstable polypeptide chains into robust therapeutics and allowing for the development of protease-resistant drugs with improved in vivo characteristics, including increased potency and circulation stability.