We begin the tutorial by displaying the C-terminal fragment of the M pro (substrate) as sticks and the adjacent M pro protein as a van der Waals surface, to visualize how the substrate fits into the binding pockets of the protein active site. The substrate adopts a kinked conformation, in which the phenyl group of Phe 309 points toward the backbone of Phe 305. The proximity of Phe 309 and Phe 305 inspired us to connect the phenyl group of the Phe 309 with the backbone of Phe 305 to form a cyclic peptide (Figure ). By cyclizing the linear substrate, we aim to lock the peptide substrate into its bound conformation and increase its stability toward proteolysis. Furthermore, cyclic peptides often exhibit greater cell permeability than the corresponding linear analogues, which is critical because M pro constitutes an intracellular target. Figure . The interaction between the substrate (sticks) and the active site of the protein (grey surface). The green oval illustrates the concept of connecting the phenyl group of Phe 309 to the backbone of Phe 305.