Hypercholesterolemia, characterized by increased plasma low-density lipoprotein cholesterol, is a major determinant of the risk of cardiovascular disease (the leading cause of global mortality). Unfortunately, the commonly known cholesterol-lowering drugs are not effective enough to obtain the recommended cholesterol levels for many people. PCSK9 plays a critical role in cholesterol metabolism, and thus its inhibition emerged as a novel therapeutic target for hypercholesterolemia. This project aims at developing small peptide-based PCSK9 inhibitors on the basis of natural polypeptides inhibiting PCSK9 activity. To achieve this goal, we need to identify key structural elements of polypeptides interacting with PCSK9 using state of the art techniques, including molecular modeling and hydrogen/ deuterium exchange mass spectrometry. This knowledge will be used to further design PCSK9 inhibitors. This project will benefit our industrial partner, PhenoSwitch Bioscience Inc., because it will lead to the development of new methods to study protein-protein interactions and broaden its product range.