Macrocyclic protease inhibitors constrained into a β-strand geometry

Proteases almost universally bind to their inhibitors and substrates in such a way that the component amino acid backbone is constrained into an extended ß-strand conformation. One important general approach to inhibitor design, as discussed here, is to pre-organise the structure into this conformation. This can lead to improved potency, biostability, resistance to proteolytic degradation, and hence therapeutic potential. Here we present an overview of some different synthetic approaches that have been employed for introducing such a macrocycle, with reference to selected examples. We also briefly discuss some representative naturally occurring examples of such macrocyclic protease inhibitors.