Synthesis of new (-)-Bestatin-based inhibitor libraries reveals a novel binding mode in the S1 pocket of the essential malaria M1 metalloaminopeptidase.

The essential malarial PfA-M1 metalloaminopeptidase is a validated drug target that functions in the terminal stages of hemoglobin digestion. The natural product dipeptide mimetic, bestatin, is a potent inhibitor of PfA-M1 and provides an excellent scaffold for the development of novel research tools as well as more effective PfA-M1 inhibitors. Here we present a new, efficient and high yielding protocol for the synthesis of bestatin-derivatives from commercially available natural and unnatural N-Boc-D-amino acids. We developed a diverse library of bestatin derivatives with variants at the sidechain of either the OE+/--hydroxy-OE