Potent Inhibitors of the Plasmodium falciparum Enzymes Plasmepsin I and II Devoid of Cathepsin D Inhibitory Activity

Abstract

The hemoglobin-degrading aspartic proteases plasmepsin I (Plm I) and plasmepsin II (Plm II) of the malaria parasite Plasmodium falciparum have lately emerged as putative drug targets. A series of C(2)-symmetric compounds encompassing the 1,2-dihydroxyethylene scaffold and a variety of elongated P1/P1' side chains were synthesized via microwave-assisted palladium-catalyzed coupling reactions. Binding affinity calculations with the linear interaction energy method and molecular dynamics simulations reproduced the experimental binding data obtained in a Plm II assay with very good accuracy. Bioactive conformations of the elongated P1/P1' chains were predicted and agreed essentially with a recent X-ray structure. The compounds exhibited picomolar to nanomolar inhibition constants for the plasmepsins and no measurable affinity to the human enzyme cathepsin D. Some of the compounds also demonstrated significant inhibition of parasite growth in cell culture. To the best of our knowledge, these plasmepsin inhibitors represent the most selective reported to date and constitute promising lead compounds for further optimization.

High Antiplasmodial Activity of Novel Plasmepsins I and II Inhibitors

“…15 The best IC 50 value for the inhibition of P. falciparum was 0.4 µM, thus achieving a remarkable improvement with respect to other inhibitors of PLM II. [8][9][10][11] We also demonstrated that the removal of the Lys-PQ moiety led to a drastic reduction of the antiparasitic activity.…”

“…[9][10][11] Considering the redundancy of PLMs, 12,13 it is therefore necessary to design compounds able to inhibit two or more in this enzyme family in order to develop drugs active on P. falciparum. Some of the synthesized compounds, designed as PLM II inhibitors, are also strong inhibitors of PLM I, which is, in view of the recent literature, a prerequisite for developing new antimalarial agents.…”

Anti-malaria drug development targeting the M1 alanyl and M17 leucyl aminopeptidases

“…13,18,19 However, knockout experiments have shown that the DV plasmepsins and falcipains 2 and 2′ are individually not essential to parasite survival, and because of this redundancy between the function of these enzyme classes it has proved difficult to develop drugs that effectively block the digestive process within the DV. [21][22][23][24] Peptides produced in the DV may be further processed to dipeptides by a dipeptidyl aminopeptidase I, an orthologue of mammalian cathepsin C. 25,26 Small peptides and dipeptides may also be reduced to free aminoacids within the DV and/or transported to the parasite cytosol for processing by aminopeptidases. 20,[27][28][29][30][31][32][33] Aminopeptidases are essential in releasing aminoacids from haemoglobin-derived peptides and are thus central to the growth and development of malaria parasites in the erythrocyte.…”

A glimpse into the clinical proteome of human malaria parasites Plasmodium falciparum and Plasmodium vivax

“…PfPMT was found to be expressed in the clinical strain of the parasite and can be a potential point of therapeutic intervention. Plasmepsins I and IV, involved in hemoglobin degradation, are already present in the ring stages of Pf, indicating that hemoglobin degradation begins early in the parasite life cycle and is a promising step for therapeutic intervention [29,30]. Pf is also known to rely heavily on de novo polyamine biosynthesis [31].…”