title: Synthesis of new (-)-bestatin-based inhibitor libraries reveals a novel binding mode in the S1 pocket of the essential malaria M1 metalloaminopeptidase.
abstract: The malarial PfA-M1 metallo-aminopeptidase is considered a putative drug target. The natural product dipeptide mimetic, bestatin, is a potent inhibitor of PfA-M1. Herein we present a new, efficient, and high-yielding protocol for the synthesis of bestatin derivatives from natural and unnatural N-Boc-d-amino acids. A diverse library of bestatin derivatives was synthesized with variants at the side chain of either the α-hydroxy-β-amino acid (P1) or the adjacent natural α-amino acid (P1'). Surprisingly, we found that extended aromatic side chains at the P1 position resulted in potent inhibition against PfA-M1. To understand these data, we determined the X-ray cocrystal structures of PfA-M1 with two derivatives having either a Tyr(OMe) 15 or Tyr(OBzl) 16 at the P1 position and observed substantial inhibitor-induced rearrangement of the primary loop within the PfA-M1 pocket that interacts with the P1 side chain. Our data provide important insights for the rational design of more potent and selective inhibitors of this enzyme that may eventually lead to new therapies for malaria.
authors.affiliation: Department of Pharmacology, University of Pennsylvania, 433 South University Avenue, 304G Lynch Laboratories, Philadelphia, Pennsylvania 19104-6018, United States.
authors.forename: Geetha
authors.initials: G
authors.lastname: Velmourougane
authors.forename: Michael B
authors.initials: MB
authors.lastname: Harbut
authors.forename: Seema
authors.initials: S
authors.lastname: Dalal
authors.forename: Sheena
authors.initials: S
authors.lastname: McGowan
authors.forename: Christine A
authors.initials: CA
authors.lastname: Oellig
authors.forename: Nataline
authors.initials: N
authors.lastname: Meinhardt
authors.forename: James C
authors.initials: JC
authors.lastname: Whisstock
authors.forename: Michael
authors.initials: M
authors.lastname: Klemba
authors.forename: Doron C
authors.initials: DC
authors.lastname: Greenbaum
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018826:CD13 Antigens / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018360:Crystallography, X-Ray; D007930:Leucine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D011485:Protein Binding; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D054852:Small Molecule Libraries; D018826:CD13 Antigens; D007930:Leucine; C012211:ubenimex