We describe the design and evaluation of structural mimics of tendamistat, a 74-residue proteinaceous inhibitor of alpha-amylase. Cyclic hexapeptides were designed in which the sequence Trp-Arg-Tyr is constrained to the i + 1 to i + 3 positions of a type I beta-turn; these compounds inhibit alpha-amylase with K-i values of 14-32 mu M, significantly more tightly than related linear tri- and hexapeptides. Incorporation of the bicyclic Nagai-Sato type II beta-turn mimic opposite the Trp-Arg-Tyr sequence in a chimeric molecule leads to a weaker inhibitor. NMR studies indicate that the desired beta-turn conformation is adopted by the cyclic hexapeptides but not by the chimeric molecule, supporting the interpretation that the former are indeed acting as small molecule mimics of tendamistat.