4r76

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

spinqualitylabelsall models 4r76, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4r76 is a 12 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 1PE, CO3, R5X, SO4, ZN Related: 3ebg, 4r5v, 4r5x, 4r6t, 4r5t, 4r7m Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed 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. Two-Pronged Attack: Dual Inhibition of Plasmodium falciparum M1 and M17 Metalloaminopeptidases by a Novel Series of Hydroxamic Acid-Based Inhibitors.,Mistry SN, Drinkwater N, Ruggeri C, Sivaraman KK, Loganathan S, Fletcher S, Drag M, Paiardini A, Avery VM, Scammells PJ, McGowan S J Med Chem. 2014 Oct 24. PMID:25299353 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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