4R7M

Structure of the m17 leucyl aminopeptidase from malaria complexed with a hydroxamic acid-based inhibitor

Summary for 4R7M

• Entry DOI: 10.2210/pdb4r7m/pdb
• Related: 3EBG 4R5T 4R5V 4R5X 4R6T 4R76
• Descriptor: M17 leucyl aminopeptidase, ZINC ION, CARBONATE ION, ... (8 entities in total)
• Functional Keywords: protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Plasmodium falciparum 3D7
• Total number of polymer chains: 12
• Total formula weight: 714481.60

Authors

Drinkwater, N.,Mcgowan, S. (deposition date: 2014-08-28, release date: 2014-10-29, Last modification date: 2023-09-20)

Primary citation

Mistry, S.N.,Drinkwater, N.,Ruggeri, C.,Sivaraman, K.K.,Loganathan, S.,Fletcher, S.,Drag, M.,Paiardini, A.,Avery, V.M.,Scammells, P.J.,McGowan, S.
Two-Pronged Attack: Dual Inhibition of Plasmodium falciparum M1 and M17 Metalloaminopeptidases by a Novel Series of Hydroxamic Acid-Based Inhibitors.
J.Med.Chem., 57:9168-9183, 2014

PubMed Abstract: Plasmodium parasites, the causative agents of malaria, have developed resistance to most of our current antimalarial therapies, including artemisinin combination therapies which are widely described as our last line of defense. Antimalarial agents with a novel mode of action are urgently required. Two Plasmodium falciparum aminopeptidases, PfA-M1 and PfA-M17, play crucial roles in the erythrocytic stage of infection and have been validated as potential antimalarial targets. Using compound-bound crystal structures of both enzymes, we have used a structure-guided approach to develop a novel series of inhibitors capable of potent inhibition of both PfA-M1 and PfA-M17 activity and parasite growth in culture. Herein we describe the design, synthesis, and evaluation of a series of hydroxamic acid-based inhibitors and demonstrate the compounds to be exciting new leads for the development of novel antimalarial therapeutics.

PubMed: 25299353
DOI: 10.1021/jm501323a

Experimental method

X-RAY DIFFRACTION (2.85 Å)