Substrate Derived Peptidic α-Ketoamides as Inhibitors of the Malarial Protease PfSUB1

Abstract

Peptidic α-ketoamides have been developed as inhibitors of the malarial protease PfSUB1. The design of inhibitors was based on the best known endogenous PfSUB1 substrate sequence, leading to compounds with low micromolar to submicromolar inhibitory activity. SAR studies were performed indicating the requirement of an aspartate mimicking the P1′ substituent and optimal P1–P4 length of the non-prime part. The importance of each of the P1–P4 amino acid side chains was investigated, revealing crucial interactions and size limitations