The two primary classes of therapeutics are small molecules and protein therapeutics. It is difficult to design small molecule inhibitors of protein protein interactions and protein therapeutics have poor cell penetration due to insufficient ability to diffuse across the cell membrane. Additionally, protein and peptides are often subject to proteolytic degradation. Furthermore, small peptides (such as single alpha-helices) do not exhibit significant helicity in solution due to entropic factors: this effect diminishes binding affinity.Introducing a synthetic brace (staple) helps to lock a peptide in a specific conformation reducing conformational entropy. This approach can increase target affinity, increase cell penetration, and protect against proteolytic degradation.