Inhibition of Proprotein Convertase Subtilisin/Kexin type-9 (PCSK9) improves cardiovascular outcomes in patients requiring additional low-density lipoprotein cholesterol reduction on top of statins, but there has been limited uptake of the two commercialized PCSK9 antibody inhibitors due in part to cost and route of administration. The protein-protein interaction between PCSK9 and the low-density lipoprotein receptor which is targeted by these therapies is a large, flat surface, which has made the discovery of orally-bioavailable small molecule inhibitors highly challenging. This talk will introduce the use of macrocyclic peptides to interrupt such protein-protein interactions, and describe the discovery and early chemistry development of such a PCSK9 inhibitor.