Antimalarial evaluation of copper(II) nanohybrid solids: inhibition of plasmepsin II, a hemoglobin-degrading malarial aspartic protease from Plasmodium falciparum

• Published in: Journal of biological inorganic chemistry 2010-03, Vol.15 (3), p.373-385
• Main Authors: Mohapatra, Subash Chandra, Tiwari, Hemandra Kumar, Singla, Manisha, Rathi, Brijesh, Sharma, Arun, Mahiya, Kuldeep, Kumar, Mukesh, Sinha, Saket, Chauhan, Shyam Singh
• Format: Article
• Language: English
• Subjects: Antimalarials - chemistry; Antimalarials - pharmacology; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - metabolism; Biochemistry; Biomedical and Life Sciences; Cathepsin D - metabolism; Copper - chemistry; Copper - pharmacology; Erythrocytes - parasitology; Hemoglobins - metabolism; Hep G2 Cells; Humans; Life Sciences; Malaria, Falciparum - drug therapy; Microbiology; Nanostructures - chemistry; Nanostructures - ultrastructure; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Original Paper; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Protozoan Proteins - antagonists & inhibitors; Protozoan Proteins - metabolism; Spectrum Analysis
• ISSN: 0949-8257; 1432-1327
• DOI: 10.1007/s00775-009-0610-9

A new class of copper(II) nanohybrid solids, LCu(CH₃COO)₂ and LCuCl₂, have been synthesized and characterized by transmission electron microscopy, dynamic light scattering, and IR spectroscopy, and have been found to be capped by a bis(benzimidazole) diamide ligand (L). The particle sizes of these nanohybrid solids were found to be in the ranges 5-10 and 60-70 nm, respectively. These nanohybrid solids were evaluated for their in vitro antimalarial activity against a chloroquine-sensitive isolate of Plasmodium falciparum (MRC 2). The interactions between these nanohybrid solids and plasmepsin II (an aspartic protease and a plausible novel target for antimalarial drug development), which is believed to be essential for hemoglobin degradation by the parasite, have been assayed by UV-vis spectroscopy and inhibition kinetics using Lineweaver-Burk plots. Our results suggest that these two compounds have antimalarial activities, and the IC₅₀ values (0.025-0.032 μg/ml) are similar to the IC₅₀ value of the standard drug chloroquine used in the bioassay. Lineweaver-Burk plots for inhibition of plasmepsin II by LCu(CH₃COO)₂ and LCuCl₂ show that the inhibition is competitive with respect to the substrate. The inhibition constants of LCu(CH₃COO)₂ and LCuCl₂ were found to be 10 and 13 μM, respectively. The IC₅₀ values for inhibition of plasmepsin II by LCu(CH₃COO)₂ and LCuCl₂ were found to be 14 and 17 μM, respectively. Copper(II) metal capped by a benzimidazole group, which resembles the histidine group of copper proteins (galactose oxidase, β-hydroxylase), could provide a suitable anchoring site on the nanosurface and thus could be useful for inhibition of target enzymes via binding to the S1/S3 pocket of the enzyme hydrophobically. Both copper(II) nanohybrid solids were found to be nontoxic against human hepatocellular carcinoma cells and were highly selective for plasmepsin II versus human cathepsin D. The pivotal mechanism of antimalarial activity of these compounds via plasmepsin II inhibition in the P. falciparum malaria parasite is demonstrated.