CYCLIC HEXAPEPTIDES AND CHIMERIC PEPTIDES AS MIMICS OF TENDAMISTAT

We describe the design and evaluation of structural mimics of tendamis tat, a 74-residue proteinaceous inhibitor of alpha-amylase. Cyclic hex apeptides were designed in which the sequence Trp-Arg-Tyr is constrain ed to the i + 1 to i + 3 positions of a type I beta-turn; these compou nds 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-A rg-Tyr sequence in a chimeric molecule leads to a weaker inhibitor. NM R studies indicate that the desired beta-turn conformation is adopted by the cyclic hexapeptides but not by the chimeric molecule, supportin g the interpretation that the former are indeed acting as small molecu le mimics of tendamistat.