Identification and characterization of allophenylnorstatine-based inhibitors of plasmepsin II, an antimalarial target.

  title={Identification and characterization of allophenylnorstatine-based inhibitors of plasmepsin II, an antimalarial target.},
  author={Azin G. Nezami and Irene Luque and Tooru Kimura and Yoshiaki Kiso and Ernesto Freire},
  volume={41 7},
Plasmepsin II is a key enzyme in the life cycle of the Plasmodium parasites responsible for malaria, a disease that afflicts more than 300 million individuals annually. Since plasmepsin II inhibition leads to starvation of the parasite, it has been acknowledged as an important target for the development of new antimalarials. In this paper, we identify and characterize high-affinity inhibitors of plasmepsin II based upon the allophenylnorstatine scaffold. The best compound, KNI-727, inhibits… 

Structure of the aspartic protease plasmepsin 4 from the malarial parasite Plasmodium malariae bound to an allophenylnorstatine-based inhibitor.

Inhibition analysis of PmPM4 suggests the potential for allophenylnorstatine-based compounds to be effective against all species of malaria infecting humans and for the future development of a broad-based inhibitor.

Deciphering the mechanism of potent peptidomimetic inhibitors targeting plasmepsins – biochemical and structural insights

KNI‐10743 and KNI‐10333 possess significant antimalarial activity, block Hb degradation inside the food vacuole, and show no cytotoxicity on human cells; thus, they can be considered as promising candidates for further optimization.

Plasmepsin Inhibitors in Antimalarial Drug Discovery: Medicinal Chemistry and Target Validation (2000 - Present).

Future antimalarial drug discovery efforts seeking to identify plasmepin inhibitors should focus on incorporating non-haemoglobinase plasmepsins such as V, IX and X in their screening in order to maximise chances of success.

Insight into Selectivity of Peptidomimetic Inhibitors with Modified Statine Core for Plasmepsin II of Plasmodium falciparum over Human Cathepsin D

Binding of PlmII inhibitors has been modeled using the crystal structures of pfPlmII and hCatD complexes to gain insight into structural requirements underlying the target selectivity, and it was concluded that the contributions of the P2 and P3′ residues to the inhibitor’s binding affinity are responsible for the targetSelectivity.

Plasmepsins as potential targets for new antimalarial therapy

It seems clear that in order to achieve high‐antiparasitic activities in P. falciparum‐infected erythrocytes it is necessary to inhibit several of the haemoglobin‐degrading plasmepsins, which represent all classes which, to the best of the authors' knowledge, have been disclosed in journal articles to date.

Computational inhibitor design against malaria plasmepsins

Application of computational techniques, especially binding affinity prediction by the linear interaction energy method, in the development of malarial plasmepsin inhibitors has been highly successful and is discussed in detail.