Synthesis of Analogues of the Carboxyl Protease Inhibitor Pepstatin. Effect of Structure in Subsite P3 on Inhibition of Pepsin

Article abstract of DOI:10.1021/jm00349a005

A series of pepstatin analogues having minimum structural requirements for tight-binding inhibition has been synthesized and tested on porcine pepsin.Subtle changes in the geometry and size of side chains at the valine-1 position of pepstatin were found to dramatically affect inhibitor potency as well as the type of kinetic behavior observed.The inhibitors reported here can be grouped into two categories: the more potent inhibitors are slow-binding inhibitors, i.e., exhibit slow, time-dependent inhibition; the weaker inhibitors, with K_i values greater than 10^-8M, are not time-dependent inhibitors.A minimum kinetic mechanism is proposed to account for the observed kinetic behavior.